Lung immunoglobulins in the sudden infant death syndrome.

The incidence of the sudden infant death syndrome parallels that of respiratory tract infections in the paediatric community. On the basis that the aetiology of the sudden infant death syndrome may lie in an unusual response to a trivial intercurrent respiratory infection a necropsy study was carried out investigating pulmonary immunoglobulins in 16 victims of the syndrome and a series of infants (controls) who had died of non-pulmonary causes. Compared with the controls victims of the sudden infant death syndrome had grossly raised concentrations of IgG, IgM, and to a less extent IgA in lung lavage samples. In addition, pulmonary interstitial and terminal airway cells expressing these immunoglobulins were identified far more often in victims than controls. The study failed to determine whether the increased immunoglobulin concentrations were a consequence of an unusual response to a trivial infection or an expression of otherwise altered immunological control in the respiratory tract. Epidemiological evidence and the findings of this study suggest that the respiratory tract is the prime target organ in the sudden infant death syndrome.     

Interleukin-10 and sudden infant death syndrome

Uncontrolled pro-inflammatory responses to infections or bacterial toxins have been suggested to play a role in triggering the physiological events leading to sudden infant death syndrome (SIDS). We tested the hypothesis that these uncontrolled responses might be due to interactions between the gene polymorphisms inducing low levels of IL-10 and exposure to cigarette smoke. In vitro, the IL-10 (G-1082A) polymorphism was associated with low IL-10 levels and the -1082G allele was associated with high levels. The first objective was to assess the distribution of this polymorphism among SIDS infants, parents of SIDS infants and controls, and two ethnic groups: Aboriginal Australians who have a high incidence of SIDS; and Bangladeshis who in Britain have a low incidence of SIDS compared with Europeans. The second objective was to assess effects of human recombinant IL-10 on interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) responses of human leukocytes to staphylococcal toxins implicated in SIDS. The third objective was to assess IL-10 responses to endotoxin and toxic shock syndrome toxin (TSST) from leukocytes of smokers and non-smokers in relation to the IL-10 (G-1082A) polymorphism. There were major differences in the distributions of these polymorphisms between Europeans and Bangladeshis (p=0.00) and between Europeans and Aboriginal Australians (p=0.00); however, they were similar for the Bangladeshi and Aboriginal Australian subjects. There were no significant differences in the distribution of these polymorphisms among SIDS infants or parents of SIDS infants compared to control groups. IL-10 significantly reduced IL-6 and TNF-alpha responses to TSST and staphylococcal enterotoxins A and C. At 50 ng ml(-1), IL-10 significantly increased TNF-alpha but not IL-6 responses to TSST and enterotoxin A. Although IL-10 responses to endotoxin were lower from leukocytes of smokers who were homozygous for the G allele, the differences were not significant; however, significantly lower IL-10 responses were found for smokers who were homozygous for the A allele (p=0.01) and heterozygotes (p=0.04). The pooled data found smokers had significantly lower levels of IL-10 responses to TSST, but there were no significant differences for smokers compared with non-smokers for the three genotypes. The high incidence of SIDS and serious respiratory infections among Aboriginal Australian infants and the low incidence of these conditions among Bangladeshi infants might be explained in part by our findings of differences in IL-10 responses between smokers and non-smokers. The lowest levels of IL-10 responses were observed among smokers who were homozygous for the A allele which is most prevalent among the Aboriginal Australians (83%) and Bangladeshis (84%). The major difference between the risk factors for SIDS in these two groups is the level of exposure of infants to cigarette smoke associated with maternal smoking.     

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.     

Thermal environment and sudden infant death syndrome: case-control study.

OBJECTIVE--To compare the thermal environment of infants who died of the sudden infant death syndrome with that of age matched control infants. DESIGN--Case-control study. Infants who died were matched with two controls, one for age and one for age and birth weight. Thermal measurements were conducted at the death scene for cases and at the scene of last sleep for control infants, who were visited unexpectedly within four weeks of the index infant''s death on a day of similar climatic conditions. A follow up questionnaire was administered to parents of cases and controls. SETTING--The geographical area served by the professional Tasmanian state ambulance service, which includes 94% of the Tasmanian population. SUBJECTS--41 infants died of the sudden infant death syndrome at home; thermal observations at death scene were available for 28 (68%), parental questionnaire data were available for 40 (96%). 38 controls matched for age and 41 matched for age and birth weight. RESULTS--Cases had more excess thermal insulation for their given room temperature (2.3 togs) than matched controls (0.6 togs) (p = 0.009). For every excess thermal insulation unit (tog) the relative risk of the sudden infant death syndrome was 1.26 (95% confidence interval 1.05 to 1.52). The average thermal bedding value calculated from parental recall was similar to that observed by attendant ambulance officers (mean difference = 0.4 tog, p = 0.39). Cases were more likely to have been found prone (odds ratio 4.58; 1.48 to 14.11). Prone sleeping position was not a confounder or effect modifier of the relation between excess thermal insulation and the syndrome. CONCLUSIONS--Overheating and the prone sleeping position are independently associated with an increased risk of the sudden infant death syndrome. Further work on infant thermal balance and sudden infant death is required and guidelines for appropriate infant thermal care need to be developed.     

Evolution and the sudden infant death syndrome (SIDS)

Postnatal parent-infant physiological regulatory effects described in the previous paper (Part I) are viewed here as being biologically contiguous with events that occur prenatally, preparing and sensitizing the fetus to the average microenvironment into which the infant is expected, based on its evolutionary past, to be born. Following McKenna (1986), evidence (some of which is circumstantial) is presented concerning fetal hearing and fetal amniotic liquid breathing as they are affected both by maternal cardiovascular blood flow sounds in the uterus and by fluctuating maternal blood sugar levels. These data are linked in turn to the infant’s postulated postnatal responsivity to parental sensory cues, including auditory and vestibular respiratory cues that may assist infants as they “learn” to breathe and, for some, to resist a SIDS event. Data on the respiratory and vocalizing behavior of normal and hearing-impaired persons are used to show that not all forms of human breathing are innate; some forms develop with experience. These data reveal how human infants learn, for example, to coordinate higher and lower brain respiratory nuclei in the context of learning initially to cry with intent and purpose and later to speak. Voluntary, cortex-based breathing emerges at the same time that infants are most likely to die from SIDS, between 2 and 4 months of age. This switch between voluntary and involuntary breathing during both sleep (while dreaming) and wake cycles, which depends on the integration of higher cortical and lower brain stem nuclei, is complex and is possibly the basis of the human species’ unique susceptibility to SIDS—a syndrome as yet unrecognized in other species. These human infant vulnerabilities, including delayed maturity, can explain in part why natural selection ought to favor increased infant sensitivity to parental sensory cues provided by a caregiver—stimuli available in the evolving parental care environment that included parent-infant co-sleeping for more than 4–5 million years of human evolution.     

Evolution and the sudden infant death syndrome (SIDS)

This paper extends the evolutionary and developmental research model for SIDS presented in previous articles (McKenna 1990a, 1990b). Data from variety of fields were used to show why we should expect human infants to be physiologically responsive in a beneficial way to parental contact, one form of which is parent-infant co-sleeping. It was suggested that on-going sensory exchanges (touch, movement, smell, temperature, etc.) between co-sleeping parent-infant pairs might diminish the chances of an infantile cardiac-respiratory crisis (such as those suspected to occur in some SIDS cases). In this article we review recent epidemiological data and sleep research findings on SIDS to show how they relate to evolutionary and cross-cultural perspectives. Results of a preliminary study of the co-sleeping behavior of mother-infant pairs indicate that, with respect to sleep, arousal, and respiratory patterns, co-sleeping mother-infant pairs affect each other in potentially important ways. We suggest specifically that co-sleeping may shorten periods of consolidated sleep among young infants by causing them to arouse more frequently. Moreover, we suggest that partner-induced arousals might help the infant to confront sleep crises more competently. In the long run, these arousals might prevent the premature emergence of prolonged (adultlike) sleep bouts from which some infants have difficulty arousing—especially during a breathing pause or apnea.     

An infectious aetiology of sudden infant death syndrome

Due attention has been given to infectious agents and immune responses to infection in sudden infant death syndrome (SIDS). It has been acknowledged that the pathological, epidemiological and genotypic findings in SIDS infants suggest an infectious aetiology possibly being potentiated by immunoregulatory polymorphisms, however, the cause of SIDS is a mystery and remains open to debate. Consistent pathological findings are seen which display similarities to the pathogenesis of toxaemic shock and/or sepsis. The major risk factors for SIDS parallel those for increased colonization and serious bacterial infections and the natural variation in the incidence of SIDS cases is typical of an infectious disease. The roles played by viral infection, immunoregulatory genes and suspected bacterial species are discussed herein.