Sudden infant death syndrome, infection and inflammatory responses

FEMS Immunology and Medical Microbiology 42 (2004) 3–10 www.fems-microbiology.org MiniReview Sudden infant death syndrome, infection and inflammatory responses
Ashild Vege *, Torleiv Ole Rognum Institute of Forensic Medicine, University of Oslo, University Hospital, Rikshospitalet, Oslo 0027, Norway Received 17 March 2004; accepted 14 June 2004 First published online 26 June 2004 Abstract Sudden infant death syndrome (SIDS) is sudden unexpected death in infancy for which there is no explanation after review of the history, a death scene investigation and a thorough autopsy. The use of common diagnostic criteria is a prerequisite for discussing the importance of infection, inflammatory responses and trigger mechanism in SIDS. Several observations of immune stimulation in the periphery and of interleukin-6 elevation in the cerebrospinal fluid of SIDS victims explain how infections can play a role in precipitating these deaths. Finally, these findings and important risk factors for SIDS are integrated in the concept of a vicious circle for understanding the death mechanism. The vicious circle is a concept to elucidate the interactions between unfavourable factors, including deficient auto-resuscitation, and how this could result in death. Ó 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. Keywords: Sudden infant death syndrome; SIDS; Diagnostic criteria; Inflammatory response; Immunity; Interleukin; Infection 1. Classification and diagnostic criteria for sudden infant death syndrome – a prerequisite for discussing infection, inflammatory responses and trigger mechanisms In 1991, Løberg and Næss [1] showed that a large proportion of cases diagnosed as interstitial pneumonia were classified after blind re-evaluation as sudden infant death syndrome (SIDS). The dispute concerning the diagnosis was closed after forensic pathologists in the Nordic countries agreed upon common diagnostic criteria for SIDS [2], and agreed to implement them in diagnostic practice [3]. Attempts to establish a common diagnostic platform in Europe and the rest of the world have met resistance from pathologists who tend to attribute a large proportion of sudden infant deaths to infections such as myocarditis. This confusing situation gives a false impression of differences in SIDS rates around the world. The proportion of SIDS out of all sudden deaths in infancy varies between 91% and 2.5% in different populations studied [4]. * Corresponding author. Tel.: +47-23-07-1332; fax: +47-23-07-1331. E-mail address: [email protected] (
A. Vege). Divergent reporting systems in the different countries could contribute to the differences in SIDS rates around the world; furthermore, since the SIDS rates have decreased in all countries after the ‘‘back-to-sleep’’ campaigns, the ‘‘grey zone’’ has become more prominent [4]. In many of these ‘‘grey zone’’ cases it is very difficult to establish the diagnosis. In cases of subsequent deaths in siblings, there is an increasing inclination to emphasise possible predisposing factors for SIDS – so-called ‘‘genetic risk factors’’ [5]. The slogan by diMaio that one sudden infant death in a family is tragic, two are suspicious and three are homicide has been replaced by a ‘‘feeling’’ that genetic risk factors might play a role in repeated deaths in the same family. As a result, several mothers who were convicted of homicide following the deaths of two or more infants were acquitted due to reasonable doubt. What we today call SIDS is presented in Fig. 1. Approximately 40% might be explained deaths, diagnoses such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, other fatty oxidation defects, long QT-syndrome and diseases not yet discovered. The remaining SIDS cases probably represent ‘‘genuine’’ SIDS. According to the three hit model for understanding 0928-8244/$22.00 Ó 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.femsim.2004.06.015 
Vege, T. Ole Rognum / FEMS Immunology and Medical Microbiology 42 (2004) 3–10 A. 4 Possible causes of death in SIDS 1% MCAD 3% FAO 3% LQTS (cardiac ion channels ? mtDNA ? ? Neuromuscular disorders "Genuine SIDS" >50% Death mechanism: - hypoxia Others 30% Fatal triangle: -Vulnerable developmental stage -predisposition: impaired autoresuscitation -overreaction of the immune system Fig. 1. Possible causes of SIDS. Some of the cases that are now classified as SIDS may in the future be explained deaths. A little more than 50% may be ‘‘genuine SIDS’’, possibly explained by the fatal triangle. due to mutations in mtDNA, could lead to muscle weakness, which makes an infant unable to turn the head to the side when placed prone with the face down in a soft mattress. International co-operation concerning redefining SIDS and work on standardising diagnostic criteria [4] will help to facilitate world wide consensus so that statistics and results from epidemiological and laboratory studies become comparable. Experts from the USA, Australia and Europe reached consensus on diagnostic criteria for heart and lung pathology. Agreement was reached on investigations that should be performed to discover possible genetic/metabolic disorders. The international autopsy protocol for SIDS was also recommended by the meeting [4]. Such consensus is a prerequisite for evaluating the impact of infection and inflammatory response for the aetiology and pathogenesis of SIDS. 2. SIDS and the immune system SIDS [6–8], it is likely that some of the SIDS victims have inherited predispositions that contributed to their deaths. SIDS might be considered as a lethal situation in which an infant who is physiologically compromised in poorly understood ways is subjected to additive effects of a number of risk factors at a particularly vulnerable time of life [9]. These poorly understood predispositions might be polymorphisms of the interleukin-10 (IL-10) gene or polymorphisms of mitochondrial DNA (mtDNA), which lead to a vulnerable physiological state in stressful situations. Since IL-10 reduces the effects of pro-inflammatory cytokines, low levels of IL-10 might result in an over-reaction of the inflammatory/immune responses which in turn trigger the vicious circle of events leading to hypoxaemia, ending with hypoxia, coma and death (Fig. 2). In addition, the sub-normal ATP production Vicious circle of SIDS IL-10 Laryngeal immune stimulation IL-1 beta Nicotine Ineffective autoresuscitation IL-6 liberation in CNS Nicotine Imbalanced Bradycardia Slight infection Prone position Trigger Hyperthermia Severe hypoxia Death As early as 1889, Paltauf [10] published his article about ‘‘status thymicolymphaticus’’, claiming that compression of the trachea by an enlarged thymus could be the cause of death in SIDS. In this paper, he also stated that these infants had bronchitis. In the 1950s [11,12], the notion of minimal inflammation in the airways was again noted. Since then, many authors have reported that a large proportion of SIDS victims have signs of infection prior to death [13–16], and signs of slight infection are also found by microscopic examinations [17–21]. Immunoglobulins were demonstrated in lung lavage fluid by Forsyth [22]. Examinations of salivary glands [18], the tonsils [19], tracheal wall [17], duodenal mucosa [17], and larynx [23] have shown increased immune stimulation in SIDS victims. It is well known that infection and overheating are risk factors for SIDS [24]. Gene polymorphism Gasping serotonergic network Severe hypoxemia 2.1. Inflammatory response in SIDS Irregular breathing/apnea Mild hypoxemia Fig. 2. ‘‘The vicious circle of SIDS’’. Potential death mechanisms in a substantial number of the SIDS cases. 2.2. Vulnerable phase in the development of the immune system in SIDS Several studies have shown that there is a rapid development of the mucosal immune system from the second week after birth [25–27] (Fig. 3). This implies that in the first weeks and months, the infant is particularly vulnerable to various stimuli of the immune system. In a study of the synergistic effect of influenza A virus on endotoxin-induced mortality in rat pups, it was suggested that the developing immune system could be primed to respond in an exaggerated way to a second infectious challenge resulting in unexpected death [28]. A paper on neuropathology associated with stillbirth 
Vege, T. Ole Rognum / FEMS Immunology and Medical Microbiology 42 (2004) 3–10 A. 5 Fig. 4. There is a relationship between the immune response in the laryngeal mucosa and the central nervous system in SIDS. SIDS victims with high IL-6 levels in the cerebrospinal fluid also show increased number of IgA immunocytes in the mucosa and increased expression of HLA-DR antigen in the glandular epithelium [23]. These babies also were found dead in a prone position and had signs of infection prior to death. Fig. 3. Development of the mucosal IgA in salivary glands, tracheal wall and duodenal mucosa modified from [25–27]. [29] concluded that the foetal brain might be selectively vulnerable to various insults at specific stages of development and that this also has implications for SIDS. 2.3. Interleukins as the link between the peripheral immune system and the central nervous system In 1989, Gunteroth [30] proposed interleukin-1 (IL-1) as a link between the peripheral immune system and the central nervous system. It has been suggested that in addition to IL-1, there are other factors contributing to the lethargy and increased sleep associated with infection in neonates. One such factor could be allopregnanolone, a neuroactive steroid, which has potent sedative properties [31]. Lipopolysaccharide (LPS) was shown to induce an increase of the content of allopregnanolone in the brain in newborn lambs. It was suggested that its production could contribute to the somnolence in newborns and be responsible for the reduced arousal proposed to contribute to the risk of SIDS in human infants. In 1995 we found that half of the SIDS victims had elevated levels of interleukin-6 (IL-6) in their cerebrospinal fluid (csf) [32]. The concentrations of IL-6 in SIDS infants were comparable to those we found in infants dying from infectious diseases like meningitis and septicaemia. The laryngeal mucosa in SIDS victims with high csf IL-6 levels also showed signs of immune stimulation with increased numbers of IgA immunocytes and increased expression of HLA-DR in the epithelium [23]. Many of these infants also showed signs of infection prior to death and were found dead in a prone position (Fig. 4). 2.4. Interleukins and SIDS IL-6 is an endogenous pyrogen [33]. It induces fever and it has been shown that increased temperatures influence the respiration in infants [34]; this can lead to irregular breathing and an increased frequency of apnoeic episodes. Krueger et al. [35] and Walter et al. [36] demonstrated that cytokines like IL-1 are able to induce slow-wave sleep and fever in animals. In a neonatal rat model, Nelson et al. [37] found that passive heating of neonatal rat pups significantly increased the production of IL-6, but not IL-1a, and significantly increased mortality. Administration of muramyldipeptide (MDP) increased the production of IL-1a but not IL-6. MDP in combination with hyperthermia had a significant effect on mortality of the neonatal rat. It was concluded that hyperthermia combined with a surrogate of infection (MDP) influenced cytokine production [37]. Activation of the inflammatory and/or immune systems with liberation of high levels of vasoactive cytokines could play an important role. It is possible that there are defects in the immune system, which predispose to SIDS. Reid [38] suggested that the elevated immunological response in spleen and lungs of SIDS victims could be due to an initially decreased activity of the peritoneal exudate cells, resulting in an increased survival of microorganisms that eventually could invade spleen, lungs and other organs. Paulsen et al. [39] found a different binding site for mannose in cases of SIDS compared to controls and 6
Vege, T. Ole Rognum / FEMS Immunology and Medical Microbiology 42 (2004) 3–10 A. suggested that this could indicate differences in the production of antimicrobial peptides. A disturbed expression pattern of antimicrobial peptides could induce an imbalance of the local microflora with a higher density of microorganisms on the mucosa. It has also been suggested that mannan binding lectin (MBL) which is important for innate immunity is of importance in SIDS. In a study by Kilpatrick et al. [40], they did not find decreased amounts of MBL in SIDS cases compared to controls; the mean for the SIDS group was higher than that for the controls. This was interpreted as an acute phase response in the SIDS cases, indicating that these cases were preceded by bacterial infections. 2.5. Factors that increases IL-6 levels There can be several reasons for the elevated IL-6 levels. Many cell types produce this potent protein [41–46], and elevated levels of IL-6 are found in several different conditions [47–53]. Bacterial products [54,55] and various viruses [56,57] stimulate IL-6 production. High levels could be due to differences in responses to various stimuli, genetic polymorphisms, or a deficient interplay in the cytokine network, for instance with reduced production of IL-10 [58,59]. Inflammatory responses such as IL-10 can be affected by both genetic and environmental factors such as smoking. Nicotine has been shown to inhibit IL-10 production [60–63] (Fig. 2). Recent studies indicate there might be interactions between cigarette smoke and some of the IL-10 gene polymorphisms [64]. Nicotine interferes with normal autoresuscitation after apnoea and this effect is seriously aggravated when combined with interleukin1b (IL-1b) [65] (Fig. 2). Nicotine in combination with endotoxin has also been shown to cause deficient respiratory responses to apnoea and hypoxia [66]. Infection in combination with cigarette smoke might increase the infant’s vulnerability to severe infections and sudden death. Buccal epithelial cells from smokers bound significantly more potentially pathogenic bacteria than cells from non-smokers [58]. After stimulation with toxic shock syndrome toxin 1 (TSST-1) or lipopolysaccharide (LPS) leukocytes from non-smokers had higher interferon (IFN) and IL-1 responses to LPS and higher IL-10 responses to TSST-1. These findings indicate that smoking increases the SIDS risk in two ways: (1) by increasing colonisation by potentially pathogenic bacteria; (2) by altering both pro- and anti-inflammatory cytokine responses to bacterial and viral infections. In animal models, IL-10 was found to reduce the lethal effect of staphylococcal toxin [58]. In the study including smokers and non-smokers, the smokers had lower IL-10 responses to TSST-1 and LPS [58]. There is evidence that some infants have levels of the nicotine metabolite cotinine equivalent to those found in active smokers [67–69]. The risk of SIDS increases with increased exposure to cigarette smoke [69]. The ability of infants to damp down inflammatory responses induced by viruses or bacterial toxins might be significantly impaired if their IL-10 levels were constitutively low and further reduced by components of cigarette smoke. 3. SIDS and infection Prone sleeping has been well established as a main risk factor for SIDS [70–74]. When studying the age distribution in the SIDS population in the years before and after ‘‘the SIDS epidemic’’, we found that the most significant decrease had been in the age group 2 to 4 months. It was also clear that most of these young infants dying in the first period had signs of infection prior to death (Fig. 5), and most of them were found dead in a prone position (Fig. 6). In addition to prone sleeping, infections, particularly of respiratory origin, have also been considered a risk factor for SIDS [20,75–78]. It has been suggested that a fall in the numbers of sudden infant deaths over the last 10–15 years is due not to a change in the infants sleep position, but in changes in factors that lead to severe and life threatening respiratory infections [79]. These are proposed to include changes in pathogenicity of viruses, lower thresholds for medical assessment and earlier recognition of hypoxemia. Lately, Baasner and co-workers [80] have found enterovirus and parvovirus B 19 in paraffin embedded heart tissue in cases of sudden infant death syndrome by polymerase chain reaction (PCR) based diagnosis; however, conventional histological examination revealed no serious findings in the heart muscle. Further investigations are mandatory to determine if such findings really can explain the cause of death. Respiratory infections, including viral infections and pertussis [81,82], might lead to a rapidly developing hypoxemia that produces loss of consciousness within 30–45 s. It remains to be elucidated whether similar mechanisms can occur in myocardial infections, particularly if there are no signs of inflammatory reaction by histological examinations. 3.1. Laryngeal reflex, apnoea and the effect of infection Laryngeal stimulation in animals can induce prolonged and even fatal apnoea [83–85]. Stimulation of chemoreceptors and free nerve endings in the upper airways induces reflex apnoea in infants [86,87]. Lindgren et al. [88] have shown that laryngeal stimulation in lambs infected with respiratory syncytial virus (RSV) resulted in increased inhibition of minute ventilation and delayed recovery of regular breathing. RSV-infected 
Vege, T. Ole Rognum / FEMS Immunology and Medical Microbiology 42 (2004) 3–10 A. infants had significantly reinforced reflex apnoea responses compared with non-infected infants [89]. 30 3.2. Infection and impaired arousal 20 25 supine/side prone 15 Horne et al. [90] have shown that arousal from quiet sleep is impaired following an infection and that this could explain the increased risk for SIDS following an infection as shown in many studies. 7 10 5 0 25 3.3. Infection and inflammatory responses 20 Samuels argues that it is possible that SIDS is due to a rapid and severe hypoxemia following a respiratory infection, rather than being a result of an inflammatory cascade [79]. In a study of children with acute respiratory infections in a day-care centre, markedly elevated levels of IL-1b, IL-6, IL-8 and TNFa were detected in nasal lavages from the children [91]. There was also a relationship between slight clinical symptoms of infections prior to death, immune stimulation in the larynx and elevated levels of IL-6 in csf [23]. Other authors have also pointed to a connection between bacteria, bacterial toxins and an inflammatory immune response [59,92,93]. According to these authors, the hypothesis of hypoxemia as a cause of SIDS does not necessarily preclude an inflammatory reaction. Pro-inflammatory cytokines have powerful effects on physiological functions proposed to lead to death among SIDS infants: 25 20 15 no infection infection 10 5 0 25 20 15 10 5 0 <1 2 4 6 8 10 12 Fig. 5. Signs of infection prior to death, in the two time periods 1984–1989 and 1990–1996. Signs of infection were more frequent in infants younger than 4 months in the first period (P < 0:01). 15 10 5 0 <1 2 4 6 8 10 12 Fig. 6. Sleeping position in SIDS victims in the two time periods 1984–1989 and 1990–1996. Prone sleeping was significantly more prevalent in infants younger than 4 months in the first period (P < 0:01). respiratory control; cardiac arrhythmia; hypoglycaemia; hyperthermia; anaphylaxis; vascular shock [59,78]. 3.4. Bacterial species implicated in SIDS Both viruses and bacteria [59] are thought to play a role in SIDS. These are usually toxigenic bacteria that normally colonise mucosal surfaces, but under some conditions such as increased temperatures they can switch on toxin production [94,95]. While the pyrogenic toxins of Staphylococcus aureus best fit the risk factors for SIDS, there is also evidence for involvement of endotoxins of Gram-negative species, soluble toxins of the clostridia and Escherichia coli [94]. Recently, Pattison and Marshall [96] and Kerr et al. [97] proposed that there could be a link between SIDS and Helicobacter pylori. Elitsur et al. [98] concluded that H. pylori infection was most likely not associated with SIDS. We have examined stool specimens from SIDS victims, infectious deaths and accidental deaths with respect to the presence of H. pylori antigens. When separating the borderline SIDS cases from the pure SIDS cases, we found that H. pylori antigen was detected in the borderline SIDS cases at a frequency similar to that in infectious deaths [99]. This is interesting since the most common reason for diagnosing borderline SIDS is the finding of inflammatory changes considered insufficient to cause death. H. pylori is probably not the cause of SIDS, but might be considered as a marker (among others) for the deranged immune response seen in many SIDS victims. 
Vege, T. Ole Rognum / FEMS Immunology and Medical Microbiology 42 (2004) 3–10 A. 8 3.5. The vicious circle of events leading to SIDS Many of the risk factors acting in concert could start the vicious circle of SIDS (Fig. 2). An infant in a vulnerable age period with a mild infection combined with prone position, warm environments and possibly certain genetic factors could experience a series of inflammatory and physiological responses in which hypoxemia, hyperthermia and stimulation of the immune/inflammatory system rapidly lead to coma and death. In our study of cytokines in the csf, we demonstrated that there are two different populations of SIDS cases: one group with IL-6 levels similar to infants dying from serious infections; and one group with IL-6 levels comparable to violent deaths [32]. Mitchell and Williams [100] also indicate the possibility of at least two SIDS subtypes: one related to sleep position and possibly a thermal mechanism; and the other to an uncontrolled inflammatory response to infection, predominantly occurring at night when cortisol levels, another mechanism for controlling inflammatory responses, are low [101,102]. Meaningful studies of such mechanisms are dependent on careful diagnostic work. It is of paramount importance that the subgroups of SIDS studied are characterised according to internationally accepted diagnostic criteria to be able to compare results from different research groups. Whether the SIDS enigma will be solved in our time remains a question still to be answered. We think that approximately 40% of what we call SIDS today and in the years to come might be explained by as yet unknown diseases. The remaining will be solved by studies in accordance with the three hit model. References [1] Løberg, E.M. and Næss, A.B. (1991) Skyldes økningen i plutselig spedbarnsdød endrede diagnostiske kriterier? Tidsskr Nor Lægeforen 111, 2864–2866. [2] Gregersen, M., Rajs, J., Laursen, H., Baandrup, U., Frederiksen, P. and Gidlund, E. (1995) Pathologic criteria for the Nordic study of SIDS. In: Sudden Infant death Syndrome. New Trends in the Nineties (Rognum, T.O., Ed.), pp. 50–58. Scandinavian University Press, Oslo.
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