Infection and sudden unexpected death in infancy: a systematic retrospective case review

doi:10.1016/S0140-6736(08)60798-9

The Lancet

Volume 371, Issue 9627, 31 May–6 June 2008, Pages 1848-1853

https://doi.org/10.1016/S0140-6736(08)60798-9 Get rights and content

Summary

Background

The cause and mechanism of most cases of sudden unexpected death in infancy (SUDI) remain unknown, despite specialist autopsy examination. We reviewed autopsy results to determine whether infection was a cause of SUDI.

Methods

We did a systematic retrospective case review of autopsies, done at one specialist centre between 1996 and 2005, of 546 infants (aged 7–365 days) who died suddenly and unexpectedly. Cases of SUDI were categorised as unexplained, explained with histological evidence of bacterial infection, or explained by non-infective causes. Microbial isolates gathered at autopsy were classified as non-pathogens, group 1 pathogens (organisms usually associated with an identifiable focus of infection), or group 2 pathogens (organisms known to cause septicaemia without an obvious focus of infection).

Findings

Of 546 SUDI cases, 39 autopsies were excluded because of viral or pneumocystis infection or secondary bacterial infection after initial collapse and resuscitation. Bacteriological sampling was done in 470 (93%) of the remaining 507 autopsies. 2079 bacteriological samples were taken, of which 571 (27%) were sterile. Positive cultures yielded 2871 separate isolates, 484 (32%) of which showed pure growth and 1024 (68%) mixed growth. Significantly more isolates from infants whose deaths were explained by bacterial infection (78/322, 24%) and from those whose death was unexplained (440/2306, 19%) contained group 2 pathogens than did those from infants whose death was explained by a non-infective cause (27/243, 11%; difference 13·1%, 95% CI 6·9–19·2, p<0·0001 vs bacterial infection; and 8·0%, 3·2–11·8, p=0·001 vs unexplained). Significantly more cultures from infants whose deaths were unexplained contained Staphylococcus aureus (262/1628, 16%) or Escherichia coli (93/1628; 6%) than did those from infants whose deaths were of non-infective cause (S aureus: 19/211, 9%; difference 7·1%, 95% CI 2·2–10·8, p=0·005; E coli: 3/211, 1%, difference 4·3%, 1·5–5·9, p=0·003).

Interpretation

Although many post-mortem bacteriological cultures in SUDI yield organisms, most seem to be unrelated to the cause of death. The high rate of detection of group 2 pathogens, particularly S aureus and E coli, in otherwise unexplained cases of SUDI suggests that these bacteria could be associated with this condition.

Funding

Foundation for the Study of Infant Deaths.

Introduction

Sudden infant death (also known as cot death) remains one of the most common presentations of post-neonatal infant death in the UK, with many theories regarding its pathogenesis.¹ Sudden unexpected death in infancy (SUDI) is defined as the sudden and unexpected death of an infant aged less than 1 year. Such deaths are a heterogeneous group, including those in which a careful review of the death scene and a meticulous post-mortem examination will disclose a cause of death, and those that remain unexplained even after such examination. Of the deaths that remain unexplained, death might be classified as sudden infant death syndrome (SIDS) if the infant died during sleep.² In 2005, there were 268 unexplained infant deaths in England and Wales at a rate of 0·41 deaths per 1000 livebirths, making this one of the leading categories of post-neonatal infant death.³ In England and Wales all such cases are investigated on behalf of Her Majesty's Coroner (HMC) by a detailed post-mortem examination done by a paediatric pathologist in accordance with a suggested autopsy protocol that incorporates a range of associated ancillary investigations,⁴ including post-mortem sampling for microbiological examination. However, the current protocol is based mainly on expert opinion and perceived best practice, with a paucity of published objective evidence, and meaningful and appropriate interpretation of such samples could be difficult.5, 6, 7

For many decades, underlying infection has been suggested to be a possible important mechanism in SUDI, on the basis of demographic features, autopsy findings, and results of studies reporting detection of organisms.1, 8, 9 There is no doubt that infection-related disease represents the underlying cause of death in a subgroup of SUDI,9, 10, 11, 12, 13 although the proportion of cases in which post-mortem microbiological examination provides the cause of death remains uncertain. These data are derived from small case series or regional multicentre studies, with inherent variation in sampling methodology and populations. Additionally, culture results were often used to determine the cause of death, requiring empirical, but non-evidence based, assumptions to be made regarding their clinical importance. Furthermore, the appropriate interpretation of microbiological findings has major medicolegal importance, as evidenced by recent high court reviews of child death investigations.14, 15 Our aim was to examine the role of post-mortem microbiological sampling in determining the possible cause of SUDI using data derived from a large series of SUDI autopsies done at a specialist centre.

Section snippets

Study population

Great Ormond Street Hospital for Children (London, UK) is a specialist tertiary referral centre for paediatric diagnosis and treatment, including post-mortem examinations done on paediatric deaths from a wide geographical area covering the south of England. We did a systematic retrospective case review of all autopsies done on behalf of HMC for the indication of SUDI at the centre between 1996 and 2005, inclusive. Local research ethics committee approval was obtained before the start of the

Results

1516 paediatric autopsies were done between 1996 and 2005 in accordance with the common protocol, 1502 (99%) of which were done by one of six paediatric pathologists. There were 546 autopsies of infants who had died suddenly and unexpectedly, of which 39 were excluded from further analysis because of probable or identified viral or pneumocystis infection or documented development of a secondary bacterial infection after initial collapse and resuscitation. Of the remaining 507 autopsies, 379

Discussion

Although more than 70% of the post-mortem bacteriological samples that were analysed grew microbial organisms when cultured, we found that significantly more organisms that were potentially pathogenic were isolated from infants whose sudden, unexpected death could not be explained than from infants whose death was of non-infective cause. Although the reasons for this difference are unclear, our findings suggest that microbes or microbial products could be related to the pathogenesis of a

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Lymphocytic choriomeningitis virus (LCMV) is a ubiquitous virus carried by rodents. It causes human disease through contact with infectious mouse faeces, urine or secretions. The virus initially infects the human respiratory tract and lungs and produces typical viral symptoms and signs. The infection is usually self-limiting and recovery is the norm. A small proportion of individuals may develop aseptic meningitis. It is hypothesised that in infancy the virus may cause respiratory tract infection through contact with mouse excreta. The infection could activate production of staphylococcal enterotoxin in babies who are colonised by Staphylococcus aureus. Indeed, a mouse animal model has shown that the combination of LCMV infection and introduction of enterotoxin B produces fatal haematogenous shock. Neither agent alone is lethal.
Pathological (and physiological) evidence indicates shock could be the underlying terminal event in SIDS (the observed tissue damage seen in the heart and diaphragmatic muscles, and apoptosis observed in the brain and brainstem of SIDS cases). These features are consistent with a haematogenous shock event. The epidemiology of SIDS is entirely consistent with a mouse-related viral zoonosis. Moreover, rural cases of SIDS tend to feature more often than urban cases and their occurrence would be consistent with the dynamics of mouse populations. Low socioeconomic living conditions (a major risk factor for SIDS) is consistent with prevalence of mouse populations and poor hygienic conditions, with overcrowding. Prone sleeping would facilitate aspiration or ingestion of infectious material from contaminated surfaces. and poor hygienic conditions, with overcrowding, and prone sleeping would facilitate aspiration or ingestion of infectious material from contaminated surfaces. The epidemiology and pathology of SIDS and the dynamics and ubiquity of mouse populations together with human serological data would support the hypothesis that LCMV is a potential candidate as a key factor in the causation of SIDS.
SIDS, prone sleep position and infection: An overlooked epidemiological link in current SIDS research? Key evidence for the “Infection Hypothesis”
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This should be a lesson for future SIDS research because absence of findings does not mean absence of infection/sepsis. In explaining why normally sterile sites in a proportion of SIDS cases yields growth of Staphylococcus aureus and/or Escherichia coli [60,61] it is conceivable that these findings could represent a “footprint” of a lethal bacteraemic episode arising from lung infection with these bacteria [62]. Importantly, both of these pathogens are over-represented in cultures taken from the respiratory tract of SUDI/SIDS cases [63].
Mainstream researchers explain the etiology of SIDS with the cardiorespiratory paradigm. This has been the focus of intense study for many decades without providing consistent supporting data to link CNS findings to epidemiological risk factors or to the usual clinicopathological findings. Despite this, and the apparent oversight of the link between prone sleep position and respiratory infection, papers citing CNS, cardiac and sleep arousal findings continue to be published. Discovery of the prone sleep position risk factor provided tangential support for the cardiorespiratory control hypothesis which defines the mainstream approach. Despite many decades of research and huge expenditure, no aetiological answer has been forthcoming. In asking why?This paper exposes some of the shortcomings regarding this apparent oversight by mainstream SIDS researchers and examines the role of respiratory infection and puts the case for the “Infection Hypothesis.” In addition, the paper provides encouragement to neuropathologists to examine the potential link between CNS findings and cardiac function (as opposed to respiratory function) in relation to infection and to examine possible correlates between CNS findings and established risk factors such as recent infection, contaminated sleeping surfaces, maternal/obstetric/higher birth, ethnicity, non-breast-feeding, male gender, etc. or with the usual gross pathological findings of SIDS (intrathoracic petechial hemorrhages, liquid blood, congested lungs). The shortcomings exposed through this review invite questions over current research directions and hopefully encourage research into other more plausible hypotheses, such as the infection paradigm.
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  Mainstream SIDS researchers appear to have overlooked the key relationship between prone sleep position and infection.
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  This omission has major implications for current and future SIDS research.
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The newborn infant’s respiratory system must rapidly adapt to extra-uterine life. Neonatal rat and mouse models have been used to investigate early development of respiratory control and reactivity in both health and disease. This review highlights several rodent models of control of breathing and respiratory system development (including pulmonary function), discusses their translational strengths and limitations, and underscores the importance of creating clinically relevant models applicable to the human infant.
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To date, a distinct aetiology of SIDS is not known, so that it is usually an exclusion diagnosis. Among the hypotheses advanced concerning its causes there’s infections/sepsis, based on the isolation of several bacteria and viruses in blood and tissue samples from unexpectedly dead infants [40,41,44–51]. The pathogenic mechanism underlying sudden death is still poorly clear, although many works suggest a role of isolated toxigenic bacteria in shock onset, directly or by means of the toxins produced.
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A systematic review exploring the relationship between infection and sudden unexpected death between 2000 and 2016: A forensic perspective
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The most significant organisms associated with sepsis in SUDI were; S. aureus, E. coli, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae and Neisseria meningitidis. There was a significant difference (p < 0.0001) between cultures from sepsis related SUDI (n = 322) and cultures from infants with a non-infective cause of death (n = 243) [8]. The role of S. pneumoniae in sepsis associated SUDI was highlighted in a case where a ten week old infant displayed bone and soft tissue injuries (eventually declared accidental).
Death due to infectious diseases is a major health concern worldwide. This is of particular concern in developing countries where poor-socio economic status and a lack of healthcare resources contribute to the high burden of disease. In some cases death due to infection can be acute and aggressive, and death may occur without a diagnosis whilst the person is still alive. These deaths may ultimately lead to a medico-legal autopsy being performed. There are various mechanisms by which sudden death due to infection may occur. In addition, there are many risk factors associated with sudden death due to infection, which differ between infants and older individuals. However, it is unclear which pathogens and risk factors are most frequently associated with sudden death due to infection. Therefore a systematic review of articles and case reports published between 1 January 2000 and 30 June 2016 was undertaken in order to (1) explore the relationship between pathogens and their causative role and (2) identify the relationship between predisposing and/or risk factors associated with sudden death due to infection. Major databases were searched and after critical appraisal 143 articles were identified. It was found that respiratory infections and deaths involving bacterial pathogens were most commonly associated with these deaths. In addition the most common risk factors in infants were exposure to tobacco smoke and co-sleeping. In adults the most common risk factors were co-morbid conditions and illnesses. This information aids in a better understanding of these deaths and highlights the need for more research in this field, particularly in developing countries

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ArticlesInfection and sudden unexpected death in infancy: a systematic retrospective case review

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population

Results

Discussion

Lancet

Curr Diagn Pathol

Curr Diagn Pathol

Forensic Sci Int

FEMS Immunol Med Microbiol

Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach

Pediatrics

Report: unexplained deaths in infancy, 2005

Health Stat Q (Amendment)

Sudden unexpected death in infancy. A multi-agency protocol for care and investigation

A comparison of respiratory symptoms and inflammation in sudden infant death syndrome and in accidental or inflicted infant death

Am J Forensic Med Pathol

An infectious aetiology of sudden infant death syndrome

J Appl Microbiol

Articles
Infection and sudden unexpected death in infancy: a systematic retrospective case review