Autopsy report of a sudden infant death that was strongly suspicious of Kawasaki disease.

We conducted an autopsy on a 3-month-old boy in whom Kawasaki disease (KD) was strongly suspected based on the autopsy findings. The infant had a fever and was brought to a nearby clinic, where he was prescribed antipyretics and kept under observation. However, 15 days after onset of the fever, he suddenly died in bed. He exhibited no obvious redness of the lips, tongue, or conjunctiva. Membranous desquamation was present on his distal fingers. Vasculitis was observed in the coronary arteries, renal artery, splenic artery, and pulmonary vein. In addition, coronary artery aneurysms were present in the right coronary artery and left anterior descending artery. Thrombotic occlusion was observed in one aneurysm in the right coronary artery, resulting in acute myocardial infarction. The coronary artery wall showed infiltration of numerous macrophages and neutrophils. This case was classified as incomplete KD because the coronary artery aneurysm could not be demonstrated before death and was only recognized at autopsy. Pathologists and forensic scientists need to be aware that there are cases in which KD goes undiagnosed and untreated, leading to coronary artery aneurysm formation and sudden death.

A Systematic Approach to Evaluate Sudden Unexplained Death in Children.

OBJECTIVE: To evaluate in the Netherlands the national outcomes in providing cause of and insights into sudden and unexplained child deaths among children via the Postmortem Evaluation of Sudden Unexplained Death in Youth (PESUDY) procedure. STUDY DESIGN: Children aged 0-18 years in the Netherlands who died suddenly were included in the PESUDY procedure if their death was unexplained and their parents gave consent. The PESUDY procedure consists of pediatric and forensic examination, biochemical, and microbiological tests; radiologic imaging; autopsy; and multidisciplinary discussion. Data on history, modifiable factors, previous symptoms, performed diagnostics, and cause of death were collected between October 2016 and December 2021. RESULTS: In total, 212 cases (median age 11 months, 56% boys, 33% comorbidity) were included. Microbiological, toxicological, and metabolic testing was performed in 93%, 34%, and 32% of cases. In 95% a computed tomography scan or magnetic resonance imaging was done and in 62% an autopsy was performed. The cause of death was explained in 58% of cases and a plausible cause was identified in an additional 13%. Most children died from infectious diseases. Noninfectious cardiac causes were the second leading cause of death found. Modifiable factors were identified in 24% of non-sudden infant death syndrome/unclassified sudden infant death cases and mostly involved overlooked alarming symptoms. CONCLUSIONS: The PESUDY procedure is valuable and effective for determining the cause of death in children with sudden unexplained deaths and for providing answers to grieving parents and involved health care professionals.

[Lethal lymphocytic myocarditis-an underestimated diagnosis in infancy and childhood?] / Letale lymphozytäre Myokarditis ­ eine unterschätzte Diagnose im Säuglings- und Kindesalter?

In the past, histological diagnosis of (post-)viral myocarditis was based on the so-called Dallas criteria, which have been criticized because of high interobserver variability and sampling error. Immunohistochemical qualification and quantification of interstitial intramyocardial leucocytes was established and standard values concerning adults were published. Fatal casualties due to a viral myocarditis are rare as far as babies and children are concerned (sudden unexpected death in infancy; SUDI). Cases of sudden unexpected death in the first year of life are frequently regarded as sudden infant death syndrome (SIDS). To diagnose myocarditis when there are only single focal lymphocytic infiltrates in the myocardium, the number of samples taken by autopsy is relevant. But even in babies, immunohistochemical qualification and quantification of interstitial lymphocytes and macrophages can lead to standard values allowing diagnosis of myocarditis. Depending on the course of a viral infection, molecular pathological detection of viral genome in the myocardium is possible to support the diagnosis. Using the mentioned methods gradually, there are more cases of suspected SIDS, which are in fact cases of virus-induced myocarditis as cause of death. Primary enteroviruses (coxsackie viruses) and adenoviruses were found but also Epstein-Barr virus and PVB-19.

Procalcitonin is associated with sudden unexpected death in infancy due to infection.

Infection is an important cause of death during infancy worldwide and is a frequent etiology of sudden unexpected death in infancy (SUDI). Procalcitonin (PCT) is a useful marker to diagnose infection in patients, and several studies report the stability of PCT after death. The added value of a biological marker, such as the PCT level in the blood, remains controversial in investigating SUDI. The aim of this study was to determine if PCT can help clinicians determine whether infection caused SUDI. We conducted a retrospective, multicenter study with the French SUDI registry (Observatoire National des Morts Inattendues du Nourrisson; OMIN). We collected data from this registry on children who died between May 2015 and June 2021. The levels of PCT in the blood of 540 SUDI patients were measured. We compared PCT and other biological tests performed in terms of infection status, autopsy results, and cause of death using clinical and biological data compiled by pediatricians at the SUDI referral center. PCT levels were significantly higher in the children who died from infection than in those who did not (0.12 µg/L vs. 0.08 µg/L, p < 0.001). A PCT blood level exceeding 0.2 µg/L was more frequently observed when infection was present than in the absence of infection (44.3% vs. 15.4%, p < 0.001). The same data were obtained with a 0.5 µg/L cut-off (36.1% with infection vs. 9.2% without, p < 0.001).  Conclusions: PCT is a sensitive biomarker for detecting infections postmortem; thus, additional samples may be necessary during autopsy. What is known: • PCT is a stable marker postmortem and increases earlier than CRP, i.e., 2-4 h after the beginning of an infection vs. 6 h. • PCT can be measured up to 140 h after death. What is new: • PCT is a sensitive marker for detecting infection in SUDI patients postmortem. • This test can reveal an infection from non-standardized samples obtained during autopsy if such an infection was not determined before death.

The San Diego SIDS definition-20 Years on.

AIM: As it is now 20 years since the San Diego definition of sudden infant death syndrome (SIDS) was proposed, it is timely to examine the impact of this consensus statement. RESULTS: Concerns at the time were expressed that 'death scene' had been replaced by circumstances of death and so it may have been more useful to have a more inclusive statement of 'death scene, including circumstances of death'. The category of unclassified sudden infant deaths (USID) that was proposed has not been widely adopted. More disturbing, however, is the increasing failure to use either the San Diego or earlier definitions in published research, with recent studies showing that almost two-thirds of peer-reviewed SIDS publications (2019-2021) did not quote or reference internationally accepted definitions. This is a decrease of 33% from the 68% of papers that correctly used SIDS definitions in 2011. The definition is therefore not being uniformly applied and in addition, diagnostic shift is occurring, with more pathologists favouring 'undetermined' over a designation of SIDS. CONCLUSIONS: Given these developments, how can we correctly interpret conclusions relating to SIDS research, and can we accurately monitor trends in SIDS mortality? The authors would suggest that unfortunately, at present we cannot with any precision.

Changing diagnostic patterns in cases of sudden and unexpected natural death in infants and young children: 1994-2018.

AIM: To determine whether there has been a change in the incidence and type of conditions causing sudden and unexpected natural death in infants and young children in recent years. METHODS: A search was undertaken of pathology records at Forensic Science SA in Adelaide, Australia for all cases of sudden and unexpected natural death in children aged less than 10 years at the time of death over two time periods: 1994-1998 and 2014-2018. RESULTS: Overall, 136 cases were identified consisting of 81 boys and 55 girls (M:F = 16:11; age range 0-9 years). No difference was shown in the numbers of sudden unexplained deaths in infants and young children between the two time periods (80 vs. 56; p = 0.18). A trend was shown for a prominent decrease in SIDS cases (55 vs. 12) with an increase in undetermined cases, <1 year (5 vs. 18). However, when the two categories were combined there was no statistical difference between the two periods (60/80 vs. 30/56) (p = 0.26), although a decrease in numbers had occurred. CONCLUSION: Analysis of numbers of fatalities reported from medicolegal institutes should be undertaken with an awareness of the potential effect of diagnostic shift.

The added value of molecular-based diagnostics in the African forensic medical setting.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Cardiac Causes of Sudden Unexpected Infant Death and the Role of the Primary Pediatrician.

Sudden death of an infant can be from numerous causes. The leading cardiac causes include major congenital heart disease, myocarditis, cardiomyopathies, and channelopathies. There are new approaches to evaluating these patients and surviving family members. Pediatricians are a key component in support of the family, investigation of other at-risk family members, and coordination of subspecialty consultation. [Ped Ann. 2022;51(6):e228-e233.].

Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome.

BACKGROUND: Autonomic dysfunction has been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Butyrylcholinesterase (BChE) is an enzyme of the cholinergic system, a major branch of the autonomic system, and may provide a measure of autonomic (dys)function. This study was undertaken to evaluate BChE activity in infants and young children who had died from Sudden Infant Death or Sudden Unexpected Death. METHODS: In this case-control study we measured BChE activity and total protein in the eluate of 5µL spots punched from the dried blood spots taken at birth as part of the newborn screening program. Results for each of 67 sudden unexpected deaths classified by the coroner (aged 1 week-104 weeks) = Cases, were compared to 10 date of birth - and gender-matched surviving controls (Controls), with five cases reclassified to meet criteria for SIDS, including the criterion of age 3 weeks to 1 year. FINDINGS: Conditional logistic regression showed that in groups where cases were reported as "SIDS death" there was strong evidence that lower BChE specific activity (BChEsa) was associated with death (OR=0·73 per U/mg, 95% CI 0·60-0·89, P=0·0014), whereas in groups with a "Non-SIDS death" as the case there was no evidence of a linear association between BChEsa and death (OR=1·001 per U/mg, 95% CI 0·89-1·13, P=0·99). INTERPRETATION: BChEsa, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. We conclude that a previously unidentified cholinergic deficit, identifiable by abnormal -BChEsa, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. FUNDING: All funding provided by a crowd funding campaign https://www.mycause.com.au/p/184401/damiens-legacy.

Prevalence of positive toxicology analysis from the French national registry for sudden unexpected infant death (Tox-MIN).

BACKGROUND: Sudden unexpected infant death (SUID) remains the leading cause of postnatal mortality in many countries. French and international guidelines recommend a thorough examination with toxicology studies. OBJECTIVES: The main objective was to determine the prevalence of toxic detection and positive analyses. The secondary objectives were to describe the different toxics and compare children with positive (Tox+) and negative results (Tox-) with other SUID risk factors. DESIGN AND METHODS: We used the data registered from May 2015 to December 2018 by the French national SUID registry (OMIN). It collects data for all SUID cases admitted to any of the 35 participating French SUID referral centers. RESULTS: Of the 624 SUID cases registered in the OMIN, a post-mortem toxicological analysis was performed in 398 infants. Thirty-six patients (9%) were positives for expected (Etox+ (n = 19 [53%], e.g., resuscitation drugs, regular treatments) and unexpected (UTox+) (n = 17 [47%]) toxics. The unexpected toxics were opioids (n = 8), cannabis (n = 4), cocaine (n = 3), cotinine (n = 2), carbon monoxide (n = 2), caffeine (n = 2), alcohol (n = 1) and GHB (n = 1). UTox + infants had a different seasonal distribution (p = .03), a higher incidence of inappropriate sleeping position and bedding at the time of death (respectively OR 3.8, p = .037 - OR 5.4, p = .026); inadequate body hygiene (OR 10.6, p = .0005), a younger maternal age (p = .045) and a higher rate of maternal drug abuse (OR 21.9, p = .0008). CONCLUSION: The high rate of positive results warrants routine toxicology testing. The imputability of identified molecules is complicated by the presence of other known risk factors for SUID.

Sudden infant death syndrome: Melatonin, serotonin, and CD34 factor as possible diagnostic markers and prophylactic targets.

Sudden infant death syndrome (SIDS) is one of the primary causes of death of infants in the first year of life. According to the WHO's data, the global infant mortality rate is 0.64-2 per 1,000 live-born children. Molecular and cellular aspects of SIDS development have not been identified so far. The purpose of this paper is to verify and analyze the expression of melatonin 1 and 2 receptors, serotonin (as a melatonin precursor), and CD34 molecules (as hematopoietic and endothelial markers of cardiovascular damage) in the medulla, heart, and aorta in infants who died from SIDS. An immunohistochemical method was used to investigate samples of medulla, heart, and aorta tissues of infants 3 to 9 months of age who died from SIDS. The control group included children who died from accidents. It has been shown that the expression of melatonin receptors as well as serotonin and CD34 angiogenesis markers in tissues of the medulla, heart, and aorta of infants who died from SIDS is statistically lower as compared with their expression in the same tissues in children who died from accidents. The obtained data help to clarify in detail the role of melatonin and such signaling molecules as serotonin and CD34 in SIDS pathogenesis, which can open new prospects for devising novel methods for predictive diagnosis of development and targeted prophylaxis of SIDS.

Machine Learning Approaches to Determine Feature Importance for Predicting Infant Autopsy Outcome.

INTRODUCTION: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of postneonatal death. We explored whether machine learning could be used to derive data driven insights for prediction of infant autopsy outcome. METHODS: A paediatric autopsy database containing >7,000 cases, with >300 variables, was analysed by examination stage and autopsy outcome classified as 'explained (medical cause of death identified)' or 'unexplained'. Decision tree, random forest, and gradient boosting models were iteratively trained and evaluated. RESULTS: Data from 3,100 infant and young child (<2 years) autopsies were included. Naïve decision tree using external examination data had performance of 68% for predicting an explained death. Core data items were identified using model feature importance. The most effective model was XG Boost, with overall predictive performance of 80%, demonstrating age at death, and cardiovascular and respiratory histological findings as the most important variables associated with determining medical cause of death. CONCLUSION: This study demonstrates feasibility of using machine-learning to evaluate component importance of complex medical procedures (paediatric autopsy) and highlights value of collecting routine clinical data according to defined standards. This approach can be applied to a range of clinical and operational healthcare scenarios.

Gene expression profile in cases of infectious death in infancy.

BACKGROUND: Genetic predispositions in cases suffering sudden unexpected infant death have been a research focus worldwide during the past decade. Despite large efforts, there is still uncertainty concerning the molecular pathogenesis of these deaths. With genetic technology in constant development, the possibility of an alternative approach into this research field has become available, like mRNA expression studies. METHODS: In this study, we investigated mRNA gene expression in 14 cases who died suddenly and unexpectedly from infection without a history of severe illness prior to death. The control group included eight accidents, two cases of natural death, one undetermined, one case of medical malpractice, and two homicides. The study included tissue from liver, heart, and brain using Illumina whole-genome gene expression assay. RESULTS: From the array, 19 genes showed altered expression in the infectious deaths compared to controls. Tissue from the heart showed 15 genes with altered mRNA expression compared to the control group. CONCLUSIONS: Downregulation of KCNE5 in heart tissue from cases of infectious death was of particular interest. Variants of KCNE5 are associated with Brugada syndrome and sudden death and could be responsible for the fatal outcome in the group of infectious death. IMPACT: KCNE5 is downregulated in tissue from the heart in cases of infectious death in infancy. This study provides knowledge about the gene expression profile in cases of infectious death. Variants of a gene known to give increased risk of cardiac arrhythmia is downregulated in cases of infectious death in infancy. The results could give us better knowledge as to why some infants do not survive an infection. This study provides a candidate gene for future studies.

The multiagency approach to Sudden Unexpected Infant Deaths (SUID): eleven years' experience in the Tuscany Region.

BACKGROUND: The Sudden Unexpected Infant Death Syndrome (SUID) is one of the leading causes of mortality in the first year of life. The aim of this work was the retrospective evaluation of the incidence of SUID and the effectiveness of the multiagency approach to this phenomenon in the Tuscany Region. METHODS: Data were obtained from the regional registry of SUID cases in the period 2009-2019. The registry contains both sudden unexpected deaths in the first week of life (Sudden Unexpected Early Neonatal Deaths - SUEND), and those occurring after the first week up to 1 year of age (SUID). RESULTS: In this timeframe a total of 73 sudden unexpected deaths occurred in our region; 32 were Unexplained (i.e. Sudden Infant Death Syndrome - SIDS), 24 Explained, 10 Undetermined, and 7 SUEND. Autopsies were performed in 91% of cases, and in 95% of these by three groups of selected pathologists according to our protocol. We found a low incidence of SUID (0.21 ‰), and SIDS deaths accounted for 0.1‰ of live births (48% of cases) with a high prevalence of infants of non-Italian ethnicity (38% of cases). Bereaved families were able to receive psychological support from mental health professionals and have contact with the family association, Seeds for SIDS. Audits were organized when post-mortem examinations were not carried out or carried out incorrectly in procedural terms, and when the diagnosis was particularly uncertain. CONCLUSIONS: This paper first provides data on SUID mortality based on complete post-mortems in an Italian region. According to these findings we can state that our approach is effective both in terms of correctly performed autopsies and support for bereaved families. Future efforts are necessary to further reduce the incidence of SUID especially among non- Italian infants. An improvement action is also recommended for ensuring a more accurate and consistent picture of the circumstances of death. The final approval of the National Protocol for the management of SUID cases is therefore strongly advocated in order to improve surveillance in this specific field and abolish disparities among the Italian regions.