FEMS Immunology and Medical Microbiology 42 (2004) 53–65

www.fems-microbiology.org

MiniReview

Ethnicity, infection and sudden infant death syndrome

C. Caroline Blackwell a,*, Sophia M. Moscovis a, Ann E. Gordon b,Osama M. Al Madani b, Sharron T. Hall a,c, Maree Gleeson a,c, Rodney J. Scott a,d,

June Roberts-Thomson a,d, Donald M. Weir b, Anthony Busuttil e

a Immunology and Microbiology, Faculty of Health, David Maddison Building, School of Biomedical Sciences, University of Newcastle, and

Hunter Medical Research Institute, Newcastle, NSW 2300, Australiab Medical Microbiology, University of Edinburgh, Edinburgh, UK

c Immunology, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, NSW, Australiad Genetics, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, NSW, Australia

e Forensic Medicine Unit, University of Edinburgh, Edinburgh, UK

Received 6 April 2004; accepted 14 June 2004

First published online 23 June 2004

Abstract

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, devel-

opmental 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.

� 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.

Keywords: Sudden infant death syndrome; Indigenous populations; Aboriginal australian; Bangladeshi; Cigarette smoke; Risk factors; Inflammatory

cytokine genes; Interleukin-10

* Corresponding author. Tel.: +61-124-921-4028; fax: +61-124-921-

4023.

E-mail address: Caroline.Blackwell@newcastle.edu.au (C.C. Black-

well).

0928-8244/$22.00 � 2004 Federation of European Microbiological Societies

doi:10.1016/j.femsim.2004.06.007

1. Introduction

Before the introduction of the various campaigns to

reduce the risk factors for Sudden Infant Death Syn-drome (SIDS) in Australia, New Zealand, Britain and

. Published by Elsevier B.V. All rights reserved.

Table 1

Variation in the incidence of SIDS among ethnic groups within countries

Country Ethnic group SIDS/1000 live births Refs.

Australia Aboriginal 6.1 [1]

Non-Aboriginal 1.7

United Kingdom European 1.7 [2]

Bangladeshi 0.3

United States Total population 2 [3,4]

Oriental 0.3

Poor Afro-American 5.0

Native American 5.9

Alaskan Natives 6.3

New Zealand Maori 7.4 [5]

Non-Maori 3.6

Table 2

Identified risk factors for SIDS

Non-modifiable Modifiable

Peak age range 2–4

months

Prone sleeping

Ethnicity Overheating

Male gender Cigarette smoke exposure

Night time deaths Mild respiratory infections

Lack of breast feeding

Poor socio-economic conditions

No or late immunisation

54 C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65

the United States, the incidence of these unexplained

deaths among different ethnic groups was striking

(Table 1). The incidences among Indigenous groups

such as Aboriginal Australians, New Zealand Maorisand Native Americans were high [1,5–7] and have re-

mained so despite the dramatic decline in SIDS among

populations of European origin. Cultural and child-

rearing practices as well as socio-economic factors have

been proposed to explain the greater risk of SIDS

among Indigenous peoples; however, there are no de-

finitive data to account for the differences observed. A

careful review of SIDS cases in Indigenous and non-Indigenous infants found no evidence to support criti-

cisms that the higher rates among Indigenous children

were due to bias in diagnosis [8].

We have addressed the differences among ethnic

groups in relation to susceptibility to infection because

there is evidence from studies of populations of Eu-

ropean origin that infectious agents, particularly toxi-

genic bacteria might trigger the events leading to SIDS.The risk factors for SIDS parallel those for suscepti-

bility to infections in infants, particularly respiratory

tract infections (Table 2). In the United States, the

campaigns to reduce the risks of SIDS have been less

successful among Afro-American and Native American

groups. Among Afro-American infants, it has been

noted that the magnitudes of the differences in deaths

due to respiratory infections were similar to those forSIDS [9].

Children of Indigenous groups also have higher inci-

dences of serious respiratory tract and ear infections.

Infants in these groups are colonised earlier and more

frequently by respiratory pathogens [10–12]. The genetic,

developmental or environmental factors responsible

have not yet been identified; however, in the high-risk

groups, maternal smoking is much more prevalent thanin the low-risk groups [13,14]. Poor ventilation and other

factors such as dampness have also been associated with

high levels of bacterial flora in the home environment of

some Indigenous communities [15].

In Britain, lower socio-economic conditions are re-

ported to be an important factor relating to the risk for

SIDS [16]. Although many Asian families living in

Britain are classified in lower socio-economic groups,the incidence of SIDS among Indian, Pakistani and

Bangladeshi families was lower than in families of

European origin. Infant deaths due to respiratory in-

fections are also lower in these Asian groups than in

families of European origin [2]. In Hong Kong where

many families live in suboptimal circumstances, there

is also a very low incidence of SIDS [6] indicating

an ethnic or genetically determined protective mecha-nism against SIDS. Table 3 summarises some of the

physiological, environmental and cultural differences

among infants from European, Asian and Aboriginal

Australian ethnic groups.

Virus infection might be an important predisposing

co-factor in the series of events leading to death, but

there is little evidence that SIDS is due to any one spe-

cific viral disease [20]. Toxigenic bacteria and/or theirtoxins have been identified in SIDS infants in several

different countries (Table 4). Many of these bacteria

express molecules that act as superantigens. The cyto-

kines they induce help eliminate infection in the

non-immune host; however, if these responses are not

controlled, they can cause tissue damage or even death.

The responses are those underlying the pathology of

septic and toxic shock [50,51].

Table 4

Toxigenic bacteria and their toxins implicated in sudden death in infancy

Species Toxin Superantigen Refs.

Staphylococccus aureus Enterotoxins, TSST Yes [21–24]

Bordetella pertussis Pertussis toxin, No [25–28]

endotoxin Yes

Haemophilus influenzae Endotoxin Yes [29–31]

Clostridium perfringens Enterotoxin A Yes [32,33]

Clostridium botulinum Botulism toxin No [34–36]

Streptococcus pyogenes Pyrogenic toxins A & B Yes [30]

Escherichia coli Enterotoxins, verotoxins ? [37–42]

curlin Yes [43]

Streptococcus mitis ? Yes [44]

Helicobacter pylori Endotoxin, vacuolating toxin, urease Yes [45–48]

Pneumocystis carinii ? ? [49]

?, toxin/antigen unknown.

Table 3

Risk factors for SIDS among different ethnic groups

Factor Caucasian European Bangladeshi Aboriginal Australian Refs.

SIDS/1000 live births 2 0.3 6.1 [1,2]

Prone sleeping + ) ) [13]

Mothers who smoke (%) 25 3 75 [4,13]

IgG levels at birth + ++ ++ [17]

Bed sharing + +++ +++ [18]

Switch to circadian rhythm

(age in weeks)

8–16 12–20 ? [19]

Breast feeding + +++ +++ [3,18,19]

Bacterial colonisation + ? +++ [10,12]

), +, ++, +++, rare to common; ?, not known.

C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65 55

Among the bacterial species implicated in SIDS,

Staphylococcus aureus best fits the mathematical model

proposed by the common bacterial toxin hypothesis [52].

Staphylococcal toxins can kill healthy adults or older

children [51,53]. Staphylococcal enterotoxin A (SEA), B

(SEB), C (SEC) and the toxic shock syndrome toxin

(TSST) have been identified in the tissues from over half

of SIDS cases from five different countries [23,54].

2. Assessment of the risk factors in relation to suscepti-

bility to infection

Many of the risk factors identified in epidemiological

studies of SIDS (Table 5) could affect three stages in the

infectious process: (1) frequency or density of colonisa-tion by the toxigenic species implicated in SIDS; (2) in-

duction of temperature sensitive toxins; (3) modulation

of the inflammatory responses to infection or toxins.

3. Risk factors affecting colonisation

3.1. Prone sleeping position

Prone sleeping is a major risk factor for SIDS. In

Norway, it was demonstrated that the most significant

decrease following the campaign to discourage the prone

position was among infants between 2–4 months of age

who had signs of infection before death [55]. The prone

sleeping position results in increased numbers of bacte-

ria and an increase in the variety of species in nasal se-

cretions of infants with respiratory virus infections [56].

3.2. Age range

During the 2–4 month age range in which most

SIDS deaths occur, 80–90% of infants express the

Lewisa antigen. This antigen acts as one of the recep-

tors on epithelial cells for three species of bacteria im-

plicated in SIDS: S. aureus [57–59]; Bordetella pertussis

[60]; Clostridium perfringens [61]. The proportion of

infants expressing Lewisa decreases with age. By 18–24months, the antigen is usually found on red cells of 20–

25% of children, a proportion similar to that observed

in adults [62]. Lewisa was identified in respiratory se-

cretions from 71% of SIDS infants tested in one study

[57].

S. aureus is the most common isolate from healthy

infants in the 2–4 month age range [56,63]. Over half of

normal infants are colonised by S. aureus during theperiod in which SIDS is most prevalent [56,63], and over

60% of the isolates from these children produced one or

more pyrogenic toxins [64]. While S. aureus was isolated

Table 5

Risk factors for SIDS at major stages of the infection process

Risk factors for SIDS Bacterial colonisation Toxin induction Inflammatory control

Prone position + + ?

Age range + ? +

Ethnic group + ? +

Excess of males + ? ?

Night time death ) ) +

Virus infection + ? +

Cigarette smoke + ? +

Overheating ) + +

No breast feeding + ? +

No/late immunisation ? ? +

+, one or more effects; ), no effect; ?, not known.

56 C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65

from about 56% of healthy infants 3 months of age or

younger, 86% of SIDS infants in the same age range had

these bacteria in their respiratory tract [63]. The toxins

produced by staphylococcal isolates from SIDS infants

vary in different geographic areas. The toxins producedby isolates from Scottish infants were predominantly

SEB and SEC. In contrast, isolates from SIDS infants in

Hungary predominantly produced SEA, and SEC was

produced by only one isolate from a healthy child [24].

TSST was identified in tissues of over half of SIDS in-

fants from Australia [25].

If these toxigenic bacteria are so common in infancy,

why is SIDS not more prevalent and by what mecha-nisms have the prevention campaigns acted to reduce

the incidence of SIDS? These questions are addressed in

Section 4.

3.3. Ethnic group

Children in some Indigenous groups are colonised

earlier and more heavily by respiratory pathogens thanchildren of European origin [10–12].

3.4. Gender

In the studies by Harrison et al. [56], there was an

interaction between gender and prone sleeping in that

males sleeping prone, with or without infection, had

significantly higher counts of Gram-positive cocci (in-cluding S. aureus) compared with females.

3.5. ‘‘Passive exposure’’ to cigarette smoke

The term ‘‘passive’’ smoking implies a lower level of

exposure to cigarette smoke among infants exposed to

this environmental pollutant. There is evidence, how-

ever, that some infants have as much cotinine in theirbody fluids as active smokers [65].

Smokers are more frequently colonized by staphylo-

cocci [66]. Buccal epithelial cells (BEC) from smokers

bound significantly more S. aureus, B. pertussis, and

several Gram-negative bacteria [67]. The enhanced

binding was not associated with upregulation of cell

surface antigens observed with virus-infected cells. Pre-

treatment of cells from non-smokers with a water-solu-

ble cigarette smoke extract (CSE) significantly enhancedbacterial binding. The enhancement was observed with

CSE dilutions up to 1 in 300. Coating of mucosal sur-

faces by passive exposure to cigarette smoke in the

child’s environment might enhance attachment of a va-

riety of bacterial species [67].

3.6. Mild upper respiratory tract infection

Many SIDS infants were reported to have a mild re-

spiratory tract infection before death. Assessment of

medical records for 31 SIDS deaths in a Canadian Ab-

original population indicated the majority had symptoms

of colds, virus infections or breathing difficulties [15].

In vitro, infection with respiratory syncytial virus

(RSV), influenza A or influenza B virus significantly

enhanced binding of S. aureus and B. pertussis to theHEp-2 epithelial cell line [58,60,68,69]. Similar patterns

were observed with some Gram-negative species identi-

fied in SIDS infants [68,69]. The changes in cell surface

antigens that can act as receptors for some bacterial

species could contribute to the increased binding ob-

served [69,70]. These findings support the increased

isolation of potentially pathogenic bacteria from infants

with symptoms of virus infection [56].

3.7. Breast feeding

Glycoconjugates such as the Lewisa and Lewisb an-

tigens present in human milk can significantly reduce

binding of pathogens such as C. perfringens and S. au-

reus to epithelial cells. Breast milk also contains IgA

which can aggregate bacteria making them easier toexpel in mucus. It also contains antibodies specific for

some adhesins involved in binding to epithelial cells

[59,61] and during endemic periods has protective anti-

bodies against viral infections such as RSV [71].

C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65 57

4. Risk factors and induction of temperature sensitive

toxins

Despite common carriage of toxigenic strains of S.

aureus among normal healthy infants [64], SIDS is a rareevent. This is probably due to the limited temperature

range in which the toxins are produced, 37–40 �C. Thetemperature of the nasopharynx is usually below 37 �C[72]. It is thought that some of the risk factors for SIDS

can affect the temperature of the nasopharynx which

could result in the permissive range for toxin production

being reached. These include mild respiratory infection

and prone sleeping position. Blocking a nostril withsecretions during a viral infection or by bedding or

clothing could impede cooling due to the passage of air

over the mucosal surface. The nasal temperature in the

prone, but not the upright position, was demonstrated

to reach 37 �C in 5/30 (16.7%) children in whom there

was no evidence of respiratory tract infection [73]. The

recommendations to keep infants cool and to place them

in the supine position to sleep make sense in relation tothese findings.

5. Risk factors affecting induction or control of inflam-

mation

Autopsy findings among SIDS infants found evidence

for mild infection and associated inflammatory re-sponses in SIDS infants [74]. Inflammatory responses

occur in all infants in response to new infectious agents

against which they have no specific active or passive

immunity. If these responses are not controlled, they

could contribute to several physiological responses that

have been suggested to cause or contribute to the death

of SIDS infants: cardiac arrhythmia; poor arousal; hy-

poxia; hypoglycaemia; hyperthermia; vascular collapse;anaphylaxis [54,75].

Factors that can enhance inflammatory responses

include respiratory virus infections [76–80], additive or

synergistic effects between bacterial toxins [81], interac-

tions between bacterial toxins and products of cigarette

smoke [82,83] and hyperthermia [84].

5.1. Risk factors enhancing inflammatory responses

5.1.1. Respiratory virus infection

Most of the studies on mechanisms involved in in-

teractions between virus infection and bacterial toxins

have been carried out in animal models. Induction of

pro-inflammatory cytokines that contribute to severity

of the host’s responses to infectious agents or their

products such as endotoxin can be enhanced by co-ex-isting virus infection [76–80].

The paper in this volume by Blood-Siegfried et al.

examined the interactions between virus infection and

endotoxin in a rat pup model. The virus infection ap-

peared to prime the animals for exaggerated responses

when challenged with sublethal levels of endotoxin [80].

5.1.2. Combinations of bacterial toxins

Several toxigenic species have been identified in SIDS

infants. In vitro models have demonstrated that there

are additive or synergistic effects between bacterial tox-

ins [81]. The findings of early and dense colonisation of

Indigenous children by different species of potentially

pathogenic bacteria needs to be investigated for the

ability of components of these bacteria singly or in

combination to induce inflammatory responses.

5.1.3. Cigarette smoke

In an animal model, nicotine significantly enhanced

the lethal effect of bacterial toxins [82]. Studies with

human monocytes found that cotinine, a metabolite of

nicotine enhanced production of some inflammatory

mediators. In this model system, it was also demon-

strated that a water-soluble cigarette smoke extract en-hanced tumor necrosis factor-a (TNF-a) responses of

RSV-infected human monocytes, and it also enhanced

nitric oxide production from monocytes exposed to

TSST [83]. Smokers were found to have lower baseline

levels of the anti-inflammatory cytokine interleukin-10

(IL-10) and lower levels of IL-10 in response to stimu-

lation with either TSST or endotoxin [54].

5.1.4. Hyperthermia

In an infant rat model, hyperthermia significantly

increased production of interleukin-6 (IL-6) but not in-

terleukin-1b (IL-1b). In response to muramyl dipeptide

(MDP) which was used as a surrogate for infection, IL-

1b was significantly increased but not IL-6. MDP in

combination with hyperthermia significantly increased

mortality of the animals [84]. These results suggest onepossible mechanism underlying the protective effect

noted of the ‘‘reduce the risks of SIDS’’ campaigns

might be due to keeping infants cool, thereby reduc-

ing some of the pro-inflammatory responses to minor

infections.

5.2. The effect of risk factors on control of inflammatory

responses

The risk factors for SIDS (Table 5) can also be as-

sessed in relation to control of inflammatory responses.

Three important factors to be considered are: (1) anti-

body levels which are at their lowest during the 2–4

month age range; (2) night time cortisol levels change

dramatically during this age range in which most SIDS

deaths occur; (3) genetic control of pro- and anti-in-flammatory responses. The genetic influences will be

addressed in Section 6.

58 C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65

5.2.1. Antibody levels and the protective effects of

immunisation

Negligible levels of antibodies to common bacterial

toxins have been detected in sera of SIDS infants

compared with live healthy control infants of the sameage [85]. IgA antibodies to TSST, SEC and the en-

terotoxin A of Cl. perfringens are present in human

milk and might be important defences to neutralise the

activities of the toxins before they could cross the

mucosal barriers, thus providing passive protection for

breast fed infants. Pasteurised cow’s milk contains an-

tibodies to the staphylococcal toxins, but infant for-

mula preparations do not [86]. A sub-analysis ofsamples from a large population study of heart disease

among Asian families in Britain found that compared

to women of European origin, Asian women in the

child bearing age range had higher levels of total IgG

and IgG specific for some of the staphylococcal toxins

[87,88] (Fig. 1). As a result of transplacental transfer of

IgG, Asian infants might start life with higher levels of

antibodies against toxigenic bacteria in their environ-ment; however, Aboriginal Australian infants have

levels of IgG at birth that are significantly higher than

those found in infants of European origin [18], and the

incidence of SIDS among Aboriginal infants is much

greater than that among non-Aboriginal infants in

Australia (Table 1). Antibodies specific for bacterial

toxins present in serum of Aboriginal Australian in-

fants have not been assessed.Immunisation against diphtheria, pertussis and teta-

nus (DPT) appears to have a protective effect against

SIDS [89,90]. From October 1990, immunisation for

DPT was initiated at two months rather than three

months of age for all British infants. In an animal

model, the DPT vaccine induced antibodies to the per-

tussis toxin and also IgG antibodies cross-reactive with

some of the pyrogenic staphylococcal toxins identified in

0

20

40

60

80

100

120

140

160

total IgG anti-SEA anti-SEB

European=26 South Asian=42

mg/ml µµµµg/ml

%

Fig. 1. Serum IgG levels in European and Asian women in the New-

castle (UK) Heart Study (age range 25–45 years).

SIDS infants [91]. Following the change in immunisa-

tion schedules, there was a significant decrease in SIDS

deaths among infants over 2 months of age. The greatest

reduction in SIDS deaths in Scotland was noted at 4

months of age, a pattern that might reflect a boostereffect following primary immunisation at 2 months of

age followed by further inoculations at 3 and 4 months

[91]. Similar patterns were observed for reduction in

SIDS deaths in England and Wales [92]. The protective

effect of early immunisation might be due to an earlier

switch to a TH1 T-cell cytokine response from the in

utero dominant TH2 pattern of responses [93].

5.2.2. Cortisol levels and the peak age range for SIDS

Cortisol suppresses a broad range of inflammatory

responses. During the first two months of life there is a

steady decrease in plasma cortisol levels [94]. Significant

changes in night-time cortisol levels occur during the

period in which infants begin to exhibit adult-like

physiological patterns reflecting development of circa-

dian rhythm. Between 7–16 weeks of age, the bodytemperature of infants falls at night to 36.4 �C, similar to

that of sleeping adults [95]. Peterson and Wailoo [19]

suggested that the ‘‘immature’’ state prior to the physi-

ological switch is a risk factor for SIDS because infants

who remain in this stage longer share many of the risk

factors with SIDS infants. In contrast to this hypothesis,

Asian infants stay in the ‘‘immature’’ stage significantly

longer than infants of European origin [19], and Asianinfants in Britain have a lower incidence of SIDS than

infants of European origin.

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 temper-

ature switch. Peak responses of TNF-a, IL-1b, IL-6 and

interferon c (IFN-c) to infectious agents occur during

late evening or early morning when cortisol levels arelowest and the time during which most SIDS deaths

occur [96,97]. Levels of cortisol commensurate with

those present at night time in infants following the de-

velopmental switch (<5 lg dl�1) had little or no effect on

inflammatory responses (IL-6 and TNF-a) elicited from

human leukocytes stimulated with TSST; however, lev-

els >10 lg dl�1 found during the day or at night before

the physiological changes reduced induction of the cy-tokines [98].

Rectal temperature and urinary cortisol excretion

were measured in infants before and after immunisation

for DPT and Haemophilus influenzae b. Rectal temper-

ature increased significantly the night following immu-

nisation indicating an inflammatory response. Infants in

the ‘‘immature’’ developmental state had a significant

increase in urinary cortisol excretion at night and themorning after immunisation. Once the mature adult-like

circadian rhythm pattern had developed, immunisation

no longer caused an increase in cortisol output [99].

C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65 59

The period during which there are low levels of night-

time cortisol could be a window of vulnerability for

SIDS (Fig. 2). If the drop in night-time cortisol occurs

when the infant still has enough maternal antibodies to

neutralise viruses or toxins or after it has developed itsown antibodies, the probability of uncontrolled inflam-

matory responses is reduced. If the low levels of cortisol

occur when the infant has low levels of protective anti-

bodies, it might increase the risk of inflammatory re-

sponses that we postulate contribute to some SIDS

deaths. Remaining in the ‘‘immature’’ developmental

stage for a longer period would have several advantages

in relation to susceptibility to infection. The high levelsof cortisol to deal with pro-inflammatory responses to

new infections would provide time for the infant to

produce active immunity to environmental bacteria and

their products or to make antibodies in response to

childhood immunisations which commence at 8 weeks

of age.

6. Genetic control of inflammatory responses

Our studies on cytokine gene polymorphisms in three

ethnic groups in which there are low (Bangladeshi),

medium (European) and high (Aboriginal Australians)

incidences of SIDS indicate that there are major differ-

ences in the distribution of some polymorphisms be-

tween Europeans and the other two groups [100,101].

6.1. IL-10 gene polymorphisms

The anti-inflammatory cytokine IL-10 plays an im-

portant role in control of pro-inflammatory responses.

In animal models, it reduces the lethality of staphylo-

Fig. 2. Cortisol levels of infants in relation

coccal toxins [102]. Evidence from studies on a small

number of SIDS infants suggested there was an excess

of IL-10 polymorphisms associated with lower levels of

IL-10 [103]. Although a second study by this group

found additional data to support the original findings[104], another study on a larger sample from the

Scandinavian survey of SIDS found no association with

any IL-10 polymorphisms among the SIDS infants

tested [105,106]. In contrast to the prediction from the

genetic studies, our in vitro studies found baseline levels

of IL-10 of SIDS parents were increased compared with

those of control parents, and there were no significant

differences between IL-10 responses of SIDS and con-trol parents to either TSST or endotoxin. The most

important finding in these studies was that smokers had

significantly lower levels of IL-10, both baseline levels

and those measured in response to toxin stimulation

[54].

The (G-1082A) polymorphism in the promoter se-

quence of IL-10 is associated with decreased IL-10

production [106]. The proportion of individuals with thehomozygous genotype (GG) prevalent among Europe-

ans was significantly lower among both Bangladeshis

and Aboriginal Australians. The homozygous variant

genotype (AA) found in approximately 30% of Euro-

pean populations was predominant in the other two

groups (Fig. 3). When the genotypes were assessed in

relation to smoking, leukocytes from Europeans who

were smokers with the genotypes predominant amongboth Bangladeshi and Aboriginal Australians (GA and

AA) showed significantly lower levels of IL-10 in re-

sponse to low levels of endotoxin [100]. If these re-

sponses are similar to those that occur in vivo, the

differences in the lower proportions of Bangladeshi

women who smoke (3%) compared with Aboriginal

to development of circadian rhythm.

0

1020

3040

5060

7080

90

n=118 n=32 n=123

Alle

le F

req

uen

cy (

%)

GGGAAA

European Bangladeshi Aboriginal

Fig. 3. Distribution of IL-10 gene polymorphisms (G-1082A) in Eu-

ropean, Bangladeshi and Aboriginal Australian populations.

60 C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65

Australian women (75%) could be an important factor

in explaining the differences in their respective SIDS

rates and susceptibility to severe respiratory tract in-

fections (Table 3). This is particularly important since ithas been observed that some infants have cotinine levels

equivalent to those found in active smokers [65].

6.2. IL-1b polymorphisms

In an in vitro system, we found previously that par-

ents of SIDS children had significantly higher levels of

IL-1b in response to endotoxin or TSST [54]. Amongpopulations such as Aboriginal Australians, there is a

higher incidence of meningococcal disease as well as

SIDS. Fatal meningococcal infections have been asso-

ciated with the IL-1b (C-511T) polymorphism (TT)

which results in the over-expression of IL-1b [107]. As

with the results for IL-10 above, the Bangladeshi and

Aboriginal Australian groups showed a significant dif-

ference in the distribution of the IL-1b (C-511T) poly-morphism compared with Europeans (Fig. 4). The wild

type homozygote (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-1b re-

sponses to TSST and endotoxin; however, the numbers

were too small for statistical analysis [101].

The soluble IL-1b receptor antagonist, IL-1Ra, isinvolved in non-functional binding to IL-1b which dis-

ables the interaction of IL-1b with functional IL-1 re-

0

10

20

30

40

50

60

70

80

n=122 n=32 n=123

Alle

le F

req

uen

cy (

%) CC

CTTT

European Bangladeshi Aboriginal

Fig. 4. Distribution of IL-1b gene polymorphisms (C-511T) in Euro-

pean, Bangladeshi and Aboriginal Australian populations.

ceptors present on the cell surfaces. The polymorphism

in IL-1RN (T+ 2018C) results in increased IL-1b bio-

logical activity and enhanced pro-inflammatory re-

sponses. The IL-1RN polymorphism is also associated

with increased levels of IL-1b secretion [108]; however,the mechanism responsible for this remains unknown.

Differences in the distribution of this polymorphism

among the three ethnic groups were not as dramatically

different as for the IL-1b (C-511T) polymorphism (see

Fig. 5).

6.3. Risk of inappropriately high IL-1b responses to

bacterial toxins

Individuals from different ethnic groups in our studies

were assigned to groups predicted to be at low, medium,

or high risk of strong IL-1b responses based on their

genotype for the three cytokine gene polymorphisms

assessed: IL-10 (G-1082A); IL-1b (C-511T); and IL-

1RN (T+2018C) [100] (Table 6). Based on assessment

of the IL-1b responses of the subjects in the studies, wepredicted that individuals with the combined alleles for

each cytokine, GG/CC/TT genotype (coded as AA/AA/

AA), were less likely to produce abnormally high levels

of IL-1b in response to toxins compared to individuals

with the homozygous variant genotype with the AA/TT/

CC alleles (coded as aa/aa/aa) genotype.

The distribution of the low, medium and high-risk

genotypes between ethnic groups varied significantly(p ¼ 0:000) (Table 7). There were no differences between

the non-Indigenous Australian and British Caucasian

populations (p ¼ 0:35), but both were significantly dif-

ferent from either Bangladeshi or Aboriginal Australian

populations (p ¼ 0:00). The Bangladeshi and Australian

Aboriginal populations had a predominance of indi-

viduals with a high-risk combined genotype for strong

IL-1b responses (�60%), and �25% of individuals witha medium risk. In both these populations, 5–10% of

individuals had genotypes that were of low risk of strong

IL-1b responses.

In the Caucasian Australian and British populations

over 90% of individuals had polymorphism combina-

0

10

20

30

40

50

60

70

n=117 n=32 n=122

Alle

le F

req

uen

cy (

%) TT

TCCC

European Bangladeshi Aboriginal

Fig. 5. Distribution of IL-1RN gene polymorphisms (T+ 2018C) in

European, Bangladeshi and Aboriginal Australian populations.

Table 6

Designation of ‘‘low’’, ‘‘medium’’, and ‘‘high’’ risk groups based on the

cytokine gene polymorphisms for IL-1b (C-511T), IL-1RN

(T+2018C), IL-10 (G-1082A)

CombinedRisk Group

Genotype Combination

IL-1β / IL-10 / IL-1RN

aa / aa / aa

aa / aa / Aa High

aa / aa / AA

aa / Aa / Aa

aa / Aa / AA Medium

aa / AA / AA

Aa / Aa / Aa

Aa / Aa / AA

AA / AA / AaLow

AA / AA / AA

AA, homozygous wild type for each polymorphism; Aa, hetero-

zygote; aa, homozygous variant.

C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65 61

tions associated with low or moderate pro-inflammatory

responses. The Australian population had �10% of in-

dividuals with a high-risk for uncontrolled inflammatory

responses, and <1% of the British control individualshad the high-risk cytokine gene profile.

6.4. Ethnic differences in cigarette smoking

If genetic make up were the main factor in suscepti-

bility to SIDS, the incidence of these deaths should be

similar for Aboriginal Australians and Bangladeshis.

The significantly higher incidence of SIDS among Ab-original Australian infants compared with Bangladeshis

living in the UK is evidence against this. The data in-

dicate that the genetic susceptibility alone is insufficient

Table 7

Distribution of the subjects into the combined genetic risk categories for high

and Aboriginal Australians (Aboriginal)

Ethnicity Low Medium

Australian 20 21

British 36 24

Bangladeshi 4 10

Aboriginal 6 33

Australian 20 21

Aboriginal 6 33

British 36 24

Aboriginal 6 33

Australian 20 21

Bangladeshi 4 10

British 36 24

Bangladeshi 4 10

to explain the risk for SIDS, and other genetic or en-

vironmental risk factors are required. Both groups

usually place infants to sleep in the supine position.

Both have high levels of maternal IgG at birth. Infants

in both groups are usually breast-fed and both groupshave a high proportion of co-sleeping. The major dif-

ference is the proportion of women in these two com-

munities who smoke [13,14]. If there are significant

interactions between cytokine gene polymorphisms and

components in cigarette smoke that could lead to higher

expression of pro-inflammatory and lower levels of anti-

inflammatory cytokines, these might help explain the

differences in the incidence of SIDS observed for thesetwo groups (Table 3).

Further evidence for the effect of maternal smoking

comes from a study of differences in the incidence of

SIDS among Native Americans. Risk factors in popu-

lations of Native American and Alaskan Native groups

in which there were significant differences in incidence of

SIDS were compared. Between 1984–1986 the incidence

of SIDS was 4.6 per 1000 live births among NativeAmericans Indians and Alaskan Natives in the northern

region of the United States. The incidence among In-

digenous groups in the southwestern states was 1.4 per

1000 live births. There was no significant difference in

the incidence of SIDS between populations of European

origin in the two regions with 2.1 and 1.6 per 1000 live

births in the north and southwest regions, respectively.

Differences in socio-economic status, maternal age, birthweight or prenatal care were not significant among the

Indigenous populations in the two areas. The differences

were explained by the high prevalence of maternal

smoking during pregnancy among the northern groups

and Alaskan Natives but low among the southwest

populations [7].

Further studies on how exposure to cigarette smoke

affects inflammatory responses in infants in populationswith similar genetic and socio-economic backgrounds

would provide significant insights into susceptibility to

SIDS.

IL-1b responses in Australian (non-Indigenous), British, Bangladeshi,

High P value

5 0.07

1 0.07

18 0.24

80 0.24

5 0.00

80 0.00

1 0.00

80 0.00

5 0.00

18 0.00

1 0.00

18 0.00

62 C.C. Blackwell et al. / FEMS Immunology and Medical Microbiology 42 (2004) 53–65

7. Conclusions

The risk of SIDS among infants with an infection

and the modifiable risk factors, prone sleeping, head

covered or parental smoking, was far greater than thesum of each individual factor. ‘‘These risk factors thus

modify the dangerousness of infection in infancy’’

[109].

SIDS is one of the most difficult areas of medical

research. There are no animal models that reflect all

the combinations of risk factors identified for SIDS.

There are no inbred populations to control for genetic

background when examining the effects of environ-mental factors such as cigarette smoke. Over the past

10 years there have been dramatic changes in the in-

cidence of SIDS, but these have not been uniform in all

ethnic groups. Due to the decline in SIDS deaths, large

study populations are needed to have sufficient power

to detect significant differences. Examination of the

effects of genetic, developmental and environmental

risk factors among different ethnic groups might be thekey to future progress in understanding the causes of

SIDS, rather than just the risk factors. Research into

ethnic differences will require close co-operation among

a variety of disciplines and the trust and goodwill of

families in different ethnic groups. Understanding the

interactions between genetic, environmental and de-

velopmental factors in infancy are crucial to solving

the mystery of sudden death in an otherwise healthyinfant.

Acknowledgements

This work was supported by grants from the Babes in

Arms, New Staff Grant from the University of New-

castle (Australia), the Meningitis Association of Scot-land, and The Gruss Bequest (UK). We are grateful to

colleagues who have worked with us on the various as-

pects of the projects that provided the background

for these studies–R. Bhopal, R.A. Elton, S.D. Essery,

C. Fischbacher S.A. Gulliver, V.S. James, J.W. Keeling,

D.A.C. Mackenzie, C. Meldrum, N. Molony,

M.M. Ogilvie, M.W. Raza, A.T. Saadi, N. Unwin and

M. White.

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