Children aged 1-4 years
Source: National Vital Statistics System – Mortality data (2020) via CDC WONDER Show
Children aged 5-9 years
Source: National Vital Statistics System – Mortality data (2020) via CDC WONDER Children aged 10-14 years
Source: National Vital Statistics System – Mortality data (2020) via CDC WONDER
U.S. Rates of SIDS and Other Sleep-Related Causes of Infant Death (1990—2016)3 
IntroductionGlobal childhood mortality rates in the under-5s were 44 per 1,000 live births in 2013, ranging from 2.3 in Singapore to 152.5 in Guinea-Bissau (Western sub-Saharan Africa), with rates of 4.9 per 1,000 live births in the United Kingdom (UK) (1). In England and Wales there are >5,000 deaths annually in children aged 0-19 years (2) from an estimated population of 12.9 million in this age group (3). Around 3,000 of these deaths are in infants (less than 1 year) with the majority having known serious medical conditions; such deaths are hence “expected”. Most are due to perinatal and immaturity-related conditions, which account for around 40% of cases, followed by congenital anomalies. Many of these deaths occur in the early (less than 7 days) or late neonatal (7 to 27 days) period (2). The next most commonly affected age group is adolescents, who account for around 1,000 deaths annually, with more than half being due to external, non-natural causes (2). Unexpected death occurring in an apparently healthy infant is termed “sudden unexpected death in infancy (SUDI)” and refers to such a presentation in an infant 7-365 days of age. According to most definitions, unexpected deaths in infants under 7 days of age are excluded from the SUDI category, and instead have been termed “sudden unexpected early neonatal death (SUEND)”. All cases of SUDI and SUEND require investigation to determine the cause of death. In England and Wales such cases are referred to Her Majesty’s Coroner (HMC), who will direct a post-mortem examination by a specialist pediatric pathologist. The primary rationale of the post-mortem examination, including its components and ancillary investigations, is to diagnose or exclude those natural (and non-natural) causes of death which are identifiable and to allow a specific cause of death to be provided (the specific details of the autopsy procedure are detailed in Chapter 24). Whilst many cases will subsequently be found to have died from previously unrecognized medical conditions, such as congenital anomalies or acquired natural diseases, a significant number will remain unexplained despite a complete autopsy including ancillary investigations (microbiology, virology, radiology, and metabolic studies). These cases are referred to as “unexplained SUDI”, “unascertained”, or “sudden infant death syndrome (SIDS)” according to the precise circumstances of the case and local practice, these terms by definition being diagnoses of exclusion. Excluding SIDS cases and neonatal deaths (0-27 days), for infants and children in England and Wales the most common acquired causes of natural deaths are neoplasms, diseases affecting the neurological, cardiovascular or respiratory systems, and infections (2) (Figure 25.1). It is likely that >50% of these cases may occur in infants and children with known life-limiting conditions. However, similar to in infancy, sudden unexpected death in childhood (SUDC; >1 year) also occurs, albeit less frequently than SUDI, with cases referred to the Coroner in the same manner. Following investigation, unexplained SUDC is less common than SIDS but remains a significant proportion of all childhood deaths; in England and Wales, for example, there were 212 registered SIDS cases compared to 27 unexplained SUDC cases in 2014 (4). However, globally, accurate figures regarding the proportions of explained and unexplained deaths following autopsy are difficult to establish. This is, in part, due to wide variability in the death certification process, making epidemiological evaluation unreliable (5), and a lack of large population-based studies, in particular those investigating SUDC. A recent review identified 24 published studies investigating 25 cohorts (17 in infants, 4 including both infants and children, and 4 children only) from 11 different countries; following full investigation the cause of death was found in 9-67% of SUDI and 22-86% of SUDC cases (6). In the same study, infection was reported as the commonest explanation for death overall in SUDI (52% of all the cases reported across studies) and variably reported in individual studies to account for between 15-86% of the explained cases. Of the studies in children >1 year, 36-68% of explained deaths were due to infectious causes (6). Figure 25.1:Treemap demonstrating the major causes of natural death in children (aged 28 days to 19 years) by disease/organ system in England and Wales (based on yearly average from 2009-11) (2).). Natural Disease and Unexplained DeathsMuch research over the last 40 years into SIDS has identified various environmental risk factors (7) and has led to changes in sleeping practices, with dramatic reductions in the reported incidence (8). Despite this, a significant number of deaths remain unexplained in both infants and children, and various hypotheses have been suggested to explain such cases. Developmental anomalies of the hippocampus, specifically the dentate gyrus, sometimes associated with a personal or family history of febrile seizures, are thought to represent a developmental vulnerability in infants and young children who die during sleep (9). Sudden arrhythmic deaths are considered in cases where the autopsy reveals no pathology to account for the death (10). In such cases genetic testing to identify possible channelopathies is undertaken in both the index case and close relatives, but often the yield is poor (11). It has also been suggested that clinically undiagnosed infections may be associated with apparently unexplained deaths since parents/carers often report a history of mild illness leading up to the sudden death (12); and it has been suggested that an atypical systemic inflammatory response may trigger a final common pathway in the absence of a traditional established and recognizable host-response. This chapter will focus on the autopsy features of the spectrum of natural diseases which can cause sudden death in infancy and childhood. Since a myriad of diseases could theoretically lead to death, it is not possible to describe all such entities. Therefore, we describe the more frequently encountered diseases identified at post-mortem examination, in addition to some less common but diagnostically important entities. For convenience, the chapter is divided into subsections by major organ systems/anatomical location, with the final section discussing a number of specific bacterial infections implicated in sudden death. The Respiratory SystemThe complexity of the respiratory tract is such that there are many anatomical areas that may be affected by abnormal developmental or pathological changes which have the potential to cause death in childhood. The respiratory tract is divided anatomically into the upper and lower respiratory tract (URT, LRT). The URT starts at the nostrils and mouth through the nasal passages, paranasal sinuses, pharynx, and the part of the larynx superior to the vocal cords; the LRT is defined as the portion of the larynx inferior to the vocal cords, trachea, bronchi, and acini (comprising the bronchiole, alveolar ducts, and alveoli as the functional unit of lungs). The lungs are limited by the thoracic cage and diaphragm from which they are normally separated by the pleural space. A wide range of disorders may affect any of these sites and respiratory pathology represents one of the most common organ systems responsible for natural deaths in infancy and childhood (13). Congenital and developmental anomaliesCongenital and developmental anomalies may affect any part of the respiratory tract. Some are identifiable macroscopically at autopsy whilst others require microscopic tissue examination. Gross anomalies are most likely to cause death by airway compromise (14) (Table 25.1). Histological anomalies predominantly represent abnormal development of lung parenchyma leading to death secondary to impairment of gaseous exchange (discussed in more detail later). Many gross anomalies are likely to be detected or suspected at antenatal screening and so can be managed at birth. However, some are not apparent and may present as sudden death in the early neonatal period, during infancy, or in later childhood. Congenital anomalies may be associated with malformation syndromes or may be isolated findings. Table 25.1:Examples of congenital anomalies associated with airway obstruction. (Adapted from (14).). Primary diffuse developmental pulmonary disorders (Congenital lung dysplasia). These represent a group of lethal, developmental lung diseases of uncertain etiology which usually present in the neonatal period. Acinar Dysplasia (AD) appears to represent major arrest of lung development, the lungs being abnormally small with apparent maturation arrest at the pseudoglandular or early canalicular stage (15). Lack of normal acini renders adequate gas exchange impossible, and affected infants are refractory to ventilation and die shortly after birth. The underlying cause remains unclear, but case reports revealing positive family history suggest a genetic basis in at least some cases (16). Congenital Alveolar Dysplasia (CAD) is a primary malformation of alveoli due to retardation and disturbance of normal lung growth. The lungs may be of normal size, but histological examination reveals arrest of development at the late canalicular or early saccular stage (Figure 25.2). Neonates show signs of respiratory failure and pulmonary hypertension shortly after birth. Although resuscitation is possible, they remain ventilator-dependent and die due to respiratory failure (15). Figure 25.2:Congenital alveolar dysplasia in a 21-day-old term male. Noted to be wheezy for two weeks with some feeding difficulties and found dead in his crib. Left panel: Hematoxylin- and eosin- (H&E-) stained lung showing alveolar immaturity and alveolar (more...) Alveolar Capillary Dysplasia with misalignment of pulmonary veins (ACD/MPV) is characterized by abnormal development of the pulmonary vasculature (17), with pulmonary veins, which normally sit in the interlobular septa, displaced alongside arteries and bronchioles in the bronchovascular bundles. There is an associated striking reduction in the normal subepithelial capillary bed, with capillaries being centrally positioned within widened alveolar septa, resulting in increased diffusion distance for gaseous exchange. Most infants develop progressive respiratory failure, cyanosis, and early signs of persistent pulmonary hypertension of the newborn (PPHN, see below) within 48 hours of birth; however, delayed presentation may be weeks or months later. Regardless of the age at presentation, mortality approaches 100%, with most reported cases diagnosed at autopsy (17). Most cases appear to be due to de novo heterozygous point mutations or deletions in the FOXF1 transcription factor gene or its distant enhancer region on chromosome 16q24.1 (18). Around 10% of cases also involve siblings, suggesting an inherited form of the disease (17). Congenital pulmonary lymphangectasia is a rare anomaly of the lymphatic system of the lungs which may be associated with a more generalized lymphatic maldevelopment. It is characterized by dilated lymphatic channels in the bronchovascular bundles, interlobular septa, and pleura. It can be complicated by development of chylothorax, with subsequent lung hypoplasia if occurring in utero but typically presents with respiratory distress in newborns due to recurrent chylous effusions and is uniformly fatal (15). On gross examination the lungs have a subtle cobblestone appearance with prominent interlobular septa. Inborn errors of surfactant metabolism are rare and present predominantly in infancy. More than 30 inherited autosomal recessive mutations of genes affecting surfactant production and processing have been identified, and clinical presentation and histological manifestations very much depend on the causative gene (19). The three major causative genes are those encoding for surfactant protein B (SFTPB), ATP-binding cassette transporter A3 (ABCA3), and surfactant protein C (SFTPC). SFTPB deficiency is a lethal disease of neonates resulting in a histological pattern of variant pulmonary alveolar proteinosis (PAP) with Periodic acid-Schiff (PAS)-positive granular alveolar material. Autosomal dominant ABCA3 mutations have been found to cause fatal surfactant deficiency in newborns and infants <3 months of age. Histology may show a PAP or desquamative interstitial pneumonia (DIP) pattern characterized by numerous macrophages in the alveolar spaces. The PAS-positive PAP deposits are described as being more granular in SFTPB deficiency compared to the “glassy” deposits in ABCA3 mutations (15). SFTPC deficiency typically affects older infants and shows a pattern of chronic pneumonitis of infancy (CPI) with interstitial thickening, mild inflammatory infiltrate, edema, and diffuse type II pneumocyte hyperplasia (15). Other respiratory causes of sudden neonatal deathPersistent pulmonary hypertension of the newborn (PPHN) occurs following the failure of normal pulmonary vascular relaxation during the cardiopulmonary transition from fetal to independent circulation. PPHN is associated with perinatal asphyxia, meconium aspiration syndrome, pneumonia, and pulmonary hypoplasia, with mortality rates reaching near 50%, even when treated (20). Presentation as sudden death is unusual but well described; it has been reported to account for 10% of sudden deaths in the first week of life (21). Idiopathic PPHN has normal lung parenchyma with remodeled pulmonary vasculature, and it accounts for 10-20% of all cases of PPHN (20). Massive pulmonary hemorrhage (MPH) causes death within the first few days after birth. It is more frequent in babies of low birth weight (<2,500 g) who develop severe respiratory distress, often with blood-stained secretions, immediately after birth or within the first 48 hours of life. Many associations have been described including sepsis, hyaline membrane disease, perinatal asphyxia, and cardiac defects (22). The pathogenesis of MPH remains unknown, but it is suggested to reflect a non-specific reaction to acute lung injury or reperfusion injury. Other theories include a terminal event precipitated by acute left ventricular failure (23). At autopsy the lungs are heavy and hemorrhagic (Figure 25.3) and microscopic examination reveals blood-filled alveoli with confluent hemorrhage. Figure 25.3:Massive pulmonary hemorrhage in a live-born term male who rapidly developed respiratory distress and died shortly after birth. Note the relative pallor of the heart. (From the autopsy archives at Great Ormond Street Hospital.). Meconium aspiration syndrome (MAS) is rare, occurring in around 10% of neonates born through meconium-stained amniotic fluid (MSAF). MSAF is unusual before 38 weeks’ gestation, but the incidence increases with longer gestations (24). MAS is defined clinically as respiratory distress in a neonate born through MSAF, requiring supplemental oxygen during the first two hours of life and lasting for at least 12 hours in the absence of congenital malformations of airways, lungs, or heart (25). The pathophysiology is not completely clarified but is thought to be associated with fetal distress, hence meconium passage in utero. Fetal distress induces gasping, leading to aspiration of large volumes of MSAF with rapid developmental of severe respiratory distress at birth. Aspiration of MSAF may lead to plugging of airways and surfactant dysfunction, with resultant pulmonary arterial hypertension and inflammation, all of which have a role in development of MAS (26). Histological examination of the lungs reveals meconium, vernix, abundant squames, and cellular debris in both distal and proximal airspaces. There may also be hyaline membranes, pulmonary hemorrhage, and necrosis (24). In some cases of apparently unexpected early infant deaths, histological features suggestive of MAS may be present in the absence of a definite history of MSAF and the diagnosis may not have been made prior to death. Respiratory tract infectionsUpper respiratory tract infections (URTI) are commonly caused by viruses, and although they are generally mild, severe cases and complications can occur in children and rapidly lead to death. Epiglottitis and bacterial tracheitis are commonly caused by Hemophilus influenza type b (in non-vaccinated individuals), Streptococcus, and Staphylococcus infection. Bacterial tracheitis causes exudative pseudomembrane formation; and in epiglottitis, there is diffuse edema of the epiglottis, which develops a cherry-red discoloration. Both may cause acute obstruction of the upper airways and rapid death without prompt medical attention (27). Diagnosis at autopsy is usually straightforward with macroscopic and histological abnormalities. Acute laryngotracheobronchitis (Croup) is the commonest cause of infectious upper airway obstruction in children up to 6 years old, but most cases are in those aged 1 to 2 years (27). Croup is a viral illness characterized by stridor due to subglottic edema and exudative inflammation. Parainfluenza virus (types 1, 2, 3) and Rhinovirus are the commonest etiologies followed by Enterovirus, Respiratory Syncytial virus (RSV), Influenza virus, and Human bocavirus. Measles is a rare but important cause in unvaccinated individuals (28). Aside from airway obstruction, other major risks to children are fatigue from increased work of breathing, secondary bacterial infection, and plugging of smaller airways by the inflammatory exudate, which can lead to obliterative bronchiolitis. Lower respiratory tract infections (LRTI) may be caused by bacteria, viruses, or fungal infections. Acute bronchiolitis is a major concern in infants, especially those <6 months of age. Winter epidemics occur due to RSV but other etiologies include Mycoplasma, Human Metapneumovirus, Parainfluenza virus, and Adenoviruses. Pneumonia can cause acute respiratory failure and is a relatively frequent cause of death in infants and pre-school age children, many of which are apparently “unexpected”, in that the child may not have seemed severely unwell prior to the collapse/death. Infection may be viral, bacterial, or fungal in origin. Streptococcus pneumoniae, Hemophilus influenzae, and RSV are the major life-threatening causes of pneumonia in young children worldwide. Other viral causes include Human Metapneumovirus, Parainfluenza, Measles, and Adenovirus, with death often due to secondary bacterial infection, for example with Staphylococcus aureus. This is an important cause of secondary pneumonia following viral respiratory illness and is associated with a high incidence of complications such as lung abscess and empyema. Whooping cough is caused by Bordetella pertussis, a gram-negative coccobacillus only found in humans. Globally it is ranked amongst the 10 leading causes of childhood mortality (29). It is most severe during the first six months of life, particularly in premature, non- or incompletely immunized infants, with >60% of all deaths from pertussis in infants less than 1 year. The bacterium causes direct damage to the respiratory epithelium, causing it to shed and obstruct the airways, whilst the toxin can suppress the immune response in the lung, delaying recruitment of neutrophils (29). Infection can take a fulminant course with rapid onset of respiratory distress, pulmonary hypertension, and refractory hypoxemia. Histological examination reveals a necrotizing bronchiolitis, hemorrhage, and fibrinous edema. Congenital pneumonia is caused by aspiration of infected amniotic fluid in utero from ascending genital tract infection and is commonly associated with premature rupture of membranes, chorioamnionitis, and prolonged labor. In live births it is reported in up to 20% of neonates dying within the first 48 hours of life, with premature infants being most susceptible. Escherichia coli and Group B streptococcus (GBS) are amongst the most frequently responsible organisms. Histological diagnosis requires a mononuclear cell infiltrate within the interstitium, in addition to the presence of squames and maternal neutrophils in alveolar spaces (from infected amniotic fluid). Aspiration pneumonia may cause destruction of the upper respiratory mucosa and necrotizing inflammation of the lung parenchyma due to the acidity of gastric contents. In infants it has been associated with diaphragmatic hernia, pyloric stenosis, and gastroesophageal reflux disease. In older children it is commonly associated with neurological conditions such as cerebral palsy. Diagnosis of LRTI at autopsy is based primarily on identification of significant airway or airspace inflammatory cell infiltration, with or without positive microbiological findings. It should be noted that there is some controversy regarding assessment of “severity” of such changes and their relationship to cause of death, with some providing LRTI as the likely cause in all cases in which any definite evidence is present, whereas others may interpret the findings as present but insufficient to explain the death. At present, until further “gold standard” tests are available for evaluating mechanisms of death, definitive determination of clinical significance remains impossible. Respiratory papillomatosis is associated with maternal condylomata (HPV 6 and 11 have been implicated) with vertical transmission during vaginal delivery (30). Multiple squamous papillomas usually become apparent in childhood, although they may begin in infancy. Extension into the tracheobronchial tree may lead to airway obstruction and sudden death. Histological examination reveals epithelial hyperplasia and koilocytosis. A complication of surgical management of aggressive disease is airway stenosis (31). Acquired respiratory conditionsBronchial asthma is the commonest chronic lung disease of childhood and is characterized by hypersensitivity of the airways to allergens, irritants, or viral infections, as well as cold air, exercise, and emotional upset. Exacerbations result in bronchospasm and hypersecretion of mucus, with “plugging” of airways leading to reduced gaseous exchange and ventilation-perfusion mismatch with subsequent hypoxemia. Acute exacerbations may lead to status asthmaticus, defined as asthma refractory to treatment, which is a well-recognized cause of death. However, sudden death may also occur in children previously thought to have mild disease or with minimal symptoms prior to death (32). Rarely, the first diagnosis of asthma may be made at autopsy. On macroscopic examination, typically the lungs appear hyperinflated and will often obscure the heart when viewed anteriorly. Thick mucus plugs may be seen on the cut surface with emphysematous changes due to distal air-trapping. On histological examination (Figure 25.4), mucosal edema, bronchospasm, and thick mucus plugging with eosinophils in the airways may all be seen to varying extents, all contributors to worsening hypoxia. Remodeling changes commensurate to the chronicity of the disease may be present, including smooth muscle hypertrophy, basement membrane thickening, goblet cell hyperplasia, and hypertrophy of submucosal mucus glands. There are no pathognomonic changes unique to fatal cases. Figure 25.4:Acute asthma in a 9-year-old female. H&E-stained lung (x 4) showing mucus plugging of a bronchiole and chronic changes of thickened basement membrane and smooth muscle hypertrophy. (From the autopsy archives at Great Ormond Street Hospital.). (more...) Follicular bronchitis is characterized by lymphoid hyperplasia of bronchus-associated lymphoid tissue (BALT), causing narrowing of bronchioles by external compression (Figure 25.5). It is rare in childhood and the etiology is unknown (33). Onset of symptoms may be in early infancy through to adolescence, and individuals may present with cough, dyspnea, recurrent or massive hemoptysis, failure to thrive (34), or sudden death. In adults follicular bronchitis has been associated with collagen vascular disorders, immunodeficiency, and hypersensitivity reactions. Figure 25.5:Follicular bronchitis in a 17-month-old male with symptoms of URTI, being treated with antibiotics, found dead in his cot. Left panel: H&E-stained lung (x 4). Right panel: Staining with CD20 highlights reactive lymphoid follicles encroaching into (more...) Plastic bronchitis (cast bronchitis) is characterized by the formation of gelatinous cohesive branching airway casts (35). In children it may occur in association with asthma, cystic fibrosis, or respiratory tract infections. Usually expectorated, casts may rarely lead to death from airway obstruction. Plastic bronchitis is a recognized, albeit rare, complication in children with congenital heart disease after single-ventricle palliation. In this scenario it is believed to be associated with increased pulmonary lymphatic flow, although the pathogenesis is unclear (36). AnaphylaxisAnaphylaxis is an acute life-threatening reaction to an allergen in a susceptible individual. In children it is most commonly triggered by foods, followed by insect venom (37). In those under 2 years, allergies to cows’ milk and eggs are the most frequent causes. Older children are more affected by reaction to nuts, including hazelnuts and cashews, in the pre-school years. Peanut allergy can occur at any age. Clinical signs of mucosal edema affecting the lips and tongue and bronchospasm can rapidly lead to death without prompt medical treatment. Diagnosis of anaphylaxis is, however, difficult at autopsy since there may be no specific gross or histological features, so details of the circumstances of death and medical history are essential. The most useful confirmatory test is blood showing increased levels of mast cell tryptase (samples remain useful for up to three days following death) and increased levels of total IgE or specific IgE to known or suspected allergens (38). The Cardiovascular System
Congenital heart diseaseCongenital heart disease (CHD) is the most common birth defect, affecting around 1% of live births (39): it has an estimated prevalence of 6-8 per 1,000 live births (40). With advances in antenatal diagnosis over the last 30 years, many congenital heart defects are identified prior to birth allowing time for preparation and early management of the neonate. Despite this, undiagnosed congenital heart disease still remains an important cause of sudden unexpected death, particularly during early infancy, with reports indicating that as many as 25% of babies with severe congenital heart disease may be discharged from hospital undiagnosed, and in some of these the diagnosis will first be made at autopsy (41). Most defects that are life-threatening in the neonatal period (0-27 days) have a duct-dependent systemic or pulmonary circulation issue, with signs becoming apparent on closure of the ductus arteriosus. Detailed discussion of CHD is beyond the scope of this chapter, but we present selected examples based on the types of cases more frequently encountered as sudden unexpected deaths in infancy and childhood. In general, it is recommended that the heart is examined in a systematic manner based on sequential segmental analysis, in which all connections, chambers, and relationships are evaluated and described. It should also be noted that anomalous pulmonary venous drainage may demonstrate unusual anatomical features and hence the heart, or at least its connections, should be examined in situ prior to removal. Coarctation of the Aorta (CoA) describes a narrowed segment of the aortic arch which can be of any length. The narrowing may be pre-ductal, juxta-ductal or post-ductal in location and may be part of a more complex heart defect or may occur in isolation (42). Newborn infants with CoA may be stable initially, but rapid deterioration ensues with closure of the ductus arteriosus. CoA is a particularly challenging prenatal diagnosis, even in experienced centers (41). Aortic stenosis accounts for approximately 5% of CHD (24) and may be above, below, or at the aortic valve when it may be secondary to abnormalities of the cusps. Critical aortic stenosis is life-threatening, causing obstruction to the left ventricular outflow tract and rendering the systemic circulation duct-dependent (42). At the severe end of the spectrum, aortic stenosis merges with Hypoplastic left heart syndrome (HLHS) with underdevelopment of the left side of the heart, with or without, mitral stenosis or atresia. HLHS accounts for up to 25% of all neonatal deaths from CHD (43). The etiology of HLHS is unknown and, whilst severe cases may be diagnosed during mid-trimester ultrasound scan, HLHS can evolve later in pregnancy and remain undetected until presentation shortly after birth. In these cases it has been hypothesized that an intrauterine insult in a genetically susceptible fetus occurs after embryogenesis; it may be immunological, infectious, or autoimmune in nature (43). Transposition of the great arteries (TGA) is one of the most common cyanotic congenital heart diseases in newborns and is associated with early death if untreated. If there is a co-existing large ventricular septal defect (VSD), infants may be stable initially, developing heart failure after a few weeks of life (42). TGA is a difficult antenatal diagnosis as it is usually associated with a normal four-chamber view on ultrasound and, as such, low detection rates have been reported in routine antenatal anomaly scans (41). Total anomalous pulmonary venous connection occurs when there is no connection between the pulmonary veins and the left atrium; instead the pulmonary veins drain to a common anomalous vein which joins directly to the superior or inferior vena cava or the portal vein. A patent foramen ovale or atrial septal defect is essential to provide a right-to-left shunt, allowing admixed oxygenated and deoxygenated blood to reach the left side of the heart (44). The condition is unlikely to be detected on routine prenatal anomaly scan (45) and may only become apparent in infancy. Surgical reconnection is essential in all cases (44). Sudden death may occur before diagnosis is made, where there is obstruction to pulmonary venous return as with infradiaphragmatic connection. CardiomyopathiesCardiomyopathy is defined as “a myocardial disorder in which the heart muscle is structurally and functionally abnormal in the absence of CAD, hypertension, valvular or congenital heart disease sufficient to cause the abnormality” (46). Pediatric cardiomyopathies are a heterogenous group of disorders with an annual incidence of approximately 1.13/100,000 (47). There is a bimodal incidence, with the highest peak in the first year of life and a smaller peak in adolescence (48). They are a rare but well-recognized cause of sudden unexpected death and are reported to account for around 1% of pediatric autopsies (49). Most have a genetic basis and 10-20% of pediatric cardiomyopathies are familial, necessitating referral of close relatives of the deceased for formal cardiology assessment and genetic counseling. Dilated cardiomyopathy is the commonest phenotype in childhood and is most frequently secondary to acute myocarditis or neuromuscular disease (50). However, hypocalcemia is a recognized and potentially reversible cause of dilated cardiomyopathy, especially in infants, and it has been seen as a complication of rickets (51, 52) (Figure 25.6). Figure 25.6:Dilated cardiomyopathy with endocardial fibroelastosis caused by rickets in a 9-month-old black female. (From the autopsy archives at Great Ormond Street Hospital.). Mitochondrial cardiomyopathies are estimated to occur in 20-40% of children with mitochondrial disease (53). Although cardiac screening is part of the management of individuals known to have mitochondrial disease, the first manifestation may be as sudden death. Mitochondrial cardiomyopathy commonly manifests as hypertrophic cardiomyopathy. Post-mortem diagnosis is made by identification of abnormal mitochondria within cardiac myocytes; this may be suspected on H&E and/or trichrome staining but confirmatory ultrastructure examination of cardiac myocytes is required for diagnosis. Death is most likely due to fatal arrhythmias. Histiocytoid cardiomyopathy is a rare arrhythmogenic disorder which occurs in the first two years of life and has a strong female predominance (female-to-male ratio 3:1) (54). Previously regarded as a developmental anomaly or neoplastic process, it has had many synonyms including “Purkinje cell tumor” and “oncocytic cardiomyopathy”. It has since been reclassified by the American Heart Association as a primary genetic cardiomyopathy with mitochondrial, X-linked, and autosomal recessive inheritance described (55). Clinical presentation may be with arrhythmias, dilated cardiomyopathy, and heart failure, or as sudden death. At autopsy the heart may appear grossly normal but histological examination reveals nodules of variably sized eosinophilic cells with granular cytoplasm that resemble histiocytes (Figure 25.7). Figure 25.7:Histiocytoid cardiomyopathy in a 14-month-old female with symptoms of mild URTI for two to three weeks. H&E-stained myocardium showing histocytoid cells in the lower right aspect compared to normal-appearing myocytes in the upper left corner (x (more...) Mitogenic cardiomyopathy is a recently described, distinctive form of dilated cardiomyopathy which manifests in early infancy and is invariably fatal (48). Presentation is commonly between 1 and 3 months of age with general lethargy, poor feeding, and respiratory distress, or sudden death. Histological examination reveals myocyte hypertrophy with hyperchromatic nuclei and occasional “caterpillar” nuclei. Mitotic activity is markedly increased, with a reported proliferation index of 10-20% with Ki67 immunohistochemistry compared to <1% in age-matched controls (48). Arrythmogenic right ventricular cardiomyopathy (ARVC) is a disease of the desmosomal complex which results in fibro-fatty myocardial infiltration of either ventricle leading to ventricular arrhythmias, usually manifesting in adolescence and young adulthood (56). Frequency in the general population is estimated to be 1 in 5,000, with many cases remaining asymptomatic (57). Examination of the heart reveals extensive replacement of the cardiac myocytes by adipose tissue and fibrosis (Figure 25.8). Figure 25.8:Fatty replacement of the right ventricular wall of the heart (left side of the photograph) in a 14-year-old male who collapsed whilst playing football. (From the autopsy archives at Great Ormond Street Hospital.). Cardiac channelopathiesAbnormalities in the ion channels in myocardial cell membranes can give rise to cardiac arrhythmias and can increase the risk of sudden death. Major channelopathies include long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BS), and catecholamingeric polymorphic ventricular tachycardia (CPVT) (58). In such cases the heart appears structurally and histologically normal at autopsy and no other cause of death is identified. Suggestive factors in the medical history or circumstances of death which raise the suspicion of a channelopathy-related death include a history of syncopal episodes or palpitations, or a witnessed collapse during normal daily activities. Gene sequencing is required for diagnosis, as the channelopathies are caused by mutations in genes associated with ion channels (in the case of LQTS, SQTS, and BS) or those involved with cellular metabolism of calcium ions (in the case of CPVT) (58). More than 100 mutations have been detected and most have an autosomal-dominant inheritance pattern which has implications for other family members. Genetic testing in unselected cases remains problematic, however, since the mere finding of a “variant” or “mutation” in one of the many channelopathy genes does not necessarily indicate that this was associated with functional effects or death, and in such cases evaluation of family members is also required. Acute myocarditisAcute myocarditis is inflammation of the cardiac myocytes which can result in heart failure, dilated cardiomyopathy, and sudden death, representing approximately 2% of all unexpected pediatrics deaths referred for autopsy (59). Most commonly of viral etiology, the majority were thought to be due to Enteroviruses (Coxsackie B) and Adenovirus. However, Parvovirus B19 is increasingly recognized as a cause of fatal acute myocarditis in childhood (60) and other viruses such as Influenza viruses, Cytomegalovirus (CMV), and Varicella zoster have also been implicated. Autopsy diagnosis is based on histological features, with the Dallas criteria generally accepted as the gold standard, requiring cardiac myocyte necrosis and/or degeneration with an associated inflammatory infiltrate (50) (Figure 25.9). Virology studies may be negative, particularly where the clinical course was protracted. Figure 25.9:Acute myocarditis showing edema and extensive infiltration by chronic inflammatory cells and myocyte destruction, from a 14-year-old female with a one-week history of chest pain, fever, and dyspnea (H&E x 40). (From the autopsy archives at Great (more...) Primary cardiac tumorsPrimary cardiac tumors are rare, having an overall incidence of 0.02-0.04% in the pediatric population, with 50% diagnosed in the first year of life (61). Most cases are asymptomatic and the majority of tumors will spontaneously regress. However, if the tumors are positioned in critical areas, such as the conducting system, or if they are obstructing inflow or outflow tracts, there is a high risk of sudden death. The commonest are rhabdomyomas, which account for 45% of primary cardiac tumors in children; they are often associated with tuberous sclerosis but may occur in isolation. Cardiac fibromas (Figure 25.10) account for 25-30%; these rarely regress and their infiltrative nature makes complete resection difficult, if not impossible. More than one-third of cardiac fibromas are diagnosed in infancy, presenting with congestive heart failure or cyanosis. Conduction anomalies occur in 13% of cases and sudden cardiac death is reported in 10-30% (61). Cardiac myxomas are exceedingly rare in childhood (although they represent the commonest primary cardiac tumor in adults) and diagnosis raises the possibility of Carney complex, an autosomal-dominant multiple neoplasia syndrome characterized by multiple skin lentigines, neuronal, endocrine, and multiple cardiac myxomas. Other less common tumors include cardiac lipomas and teratomas (61). Figure 25.10:Cardiac fibroma effacing the left ventricle in a 4-month-old male. (From the autopsy archives at Great Ormond Street Hospital.). Vascular causes of sudden deathCoronary artery disease (CAD) is an uncommon cause of death in childhood and may be congenital or acquired. In contrast to adult practice, most cases are due to congenital anomalies often involving the origin of the left coronary artery (LCA) (62). Coronary artery anomalies are relatively common, occurring in up to 1.2% of population, but most are of no clinical significance. They may be part of complex structural congenital heart disease or they may occur in isolation. Sudden death may transpire at any age and is thought to be due to compression of the aberrant artery at some point along its course, with restriction of coronary blood flow resulting in infarction and cardiac arrest. Post-mortem examination may reveal areas of infarcts of varying age in the distribution of the affected artery due to previous, non-lethal restriction to myocardial perfusion. Atherosclerotic CAD in childhood is only seen in homozygotes for familial hypercholesterolemia, leading to death from myocardial infarction. Individuals commonly present in infancy and childhood, with typical skin manifestations such as xanthelasma (yellowish plaques of cholesterol around the inner canthus of the eyelid), and lipid-lowering treatment can be instigated. If untreated, CAD manifests by the age of 10 years and sudden unexpected death from myocardial infarction has been reported in children as young as 3 years old (63). Kawasaki disease is a vasculitis of unknown etiology which affects small- and medium-sized muscular vessels with a predilection for coronary arteries. It is a disease of childhood, with the highest incidence in children of Asian origin and most cases occurring in those under 5 years old (64). Coronary complications may be acute, such as myocardial infarction, or chronic, such as stenosis, dilatation, and aneurysm formation; giant aneurysms (>6mm diameter) are a high risk for stenosis. Chronic complications occur in 15-25% of untreated patients compared to <10% of treated individuals (65). Sudden unexpected death can occur due to thrombotic occlusion of a giant aneurysm, and diagnosis of Kawasaki disease has been made at autopsy (66) (Figure 25.11). Figure 25.11:Kawasaki disease with thrombotic occlusion of a giant aneurysm. Left panel: Kawasaki disease with thrombotic occlusion of a giant aneurysm in the left coronary artery. Right panel: Intimal thickening and calcification seen on histology. From a previously (more...) Aortic dissection is generally regarded as a disease of adulthood, but rare cases occur in children, most often associated with congenital heart disease, chronic hypertension, or connective tissue disorders (Marfan, Ehlers-Danlos, and Loeys-Dietz syndromes, for example) (67). Inherent or acquired weakness in the medial layer of the aorta predisposes the tissue to dissection; the aorta may rupture and, depending on the site, result in cardiac tamponade, hemothorax, or hemoperitoneum. Cases have been reported in patients with no known risk factors (68). Natural Intracranial Causes of Sudden DeathCentral nervous system (CNS) infectionsMeningitis is inflammation of the leptomeninges surrounding the brain and spinal cord; it can be due to bacterial, viral, fungal, or parasitic infections. Bacterial causes are very much dependent on the age of the child; for example, neonatal meningitis is most commonly caused by GBS (Figure 25.12), Escherichia coli, and other gram-negative organisms (69). In contrast, Neisseria meningitidis is a greater risk for children >1 year old and adolescents (70) (various organisms are discussed in more detail in the infectious diseases section). Fungal meningitis is usually due to yeast-producing fungi such as Cryptococcus or Coccidiodomycosis, although it may occur with Candida sp. (71). Figure 25.12:Purulent meningitis caused by Group B streptococcal infection in a 3-day old neonate. (From the autopsy archives at Great Ormond Street Hospital.). Primary amebic meningoencephalitis (PAM) is a rare and invariably fatal disease caused by Naegleria fowleri, which is a free-living ameba found in freshwater habitats worldwide (72). Infection is via the nasal route, with ameba migration along the olfactory nerve and into the brain, with rapid development of cerebral edema leading to cerebellar herniation and death (73). PAM is rapidly fatal and diagnosis is usually made after death (72). Cerebritis describes a poorly defined area of acute inflammation within the brain, usually caused by pyogenic (pus-producing) bacteria such as staphylococci, streptococci, and mycobacteria, or by hyphae-producing fungi such as Aspergillus sp. and Mucormycosis. Cerebritis may progress to cerebral abscess if left untreated, and it may cause death by mass effect, with cerebral edema and herniation with compression of vital brainstem structures. Sometimes, depending on the site of the abscess, there may be rupture into the ventricles, rapidly leading to death (71). Fungal brain infections are more commonly associated with immunocompromised individuals, such as those receiving chemotherapy (Figure 25.13). Figure 25.13:Aspergillus infection. Coronal section of brain showing hemorrhagic foci secondary to disseminated aspergillus infection in an 11-year-old female, following chemotherapy for non-hodgkin lymphoma. (From the autopsy archives at Great Ormond Street Hospital.). (more...) Encephalitis refers to inflammation of the substance of the brain. It is further classified as “leukoencephalitis” when only the white matter is involved, “polio encephalitis” when only the grey matter is affected, and “panencephalitis” where there is both white and grey matter involvement. There are multiple etiologies, with infection being the commonest, but also autoimmune disease and paraneoplastic syndromes. Brainstem encephalitis (Figure 25.14) specifically refers to inflammation of the hindbrain and is used interchangeably with the term rhomboencephalitis (which strictly speaking pertains to the pons, cerebellum, and medulla) (74). Figure 25.14:Brainstem encephalitis in an 18-month-old boy with history of mild URTI symptoms, found dead in his cot. H&E-stained medulla showing microglial nodules and cuffing of blood vessels by lymphocytes (x 10). (From the autopsy archives at Great Ormond (more...) Of infectious causes, Listeria is the commonest, primarily affecting healthy young adults. However, certain enteroviral causes are becoming increasingly recognized worldwide, such as Enterovirus 71 (EV71) (74). EV71 causes outbreaks of hand, foot and mouth disease in children as well as upper respiratory tract infections and gastroenteritis. Neurological complications are reported in up to 25% of cases and occur around one to three weeks following the initial illness. Presentation can be precipitous, with collapse and rapid deterioration to death. Survivors may suffer long-term functional morbidity due to focal paresis, causing it to be dubbed as the “new polio” (75). Herpes simplex virus (HSV), Epstein-Barr virus (EBV), and Human herpesvirus 6 (HHV-6) are also known etiologies. Spontaneous intracranial hemorrhagesNon-traumatic intracranial hemorrhage is an uncommon cause of sudden unexpected death in infancy and childhood. Vascular anomalies, brain tumors, and congenital heart disease are the more frequently identified causes (76), but underlying hematological and connective tissue disorders may also be implicated, and in some cases no cause is identified (77) (Figure 25.15). Important vascular anomalies include arteriovenous malformations (AVM) which are defined as abnormal connections between arteries and veins. They present with hemorrhage in up to 80% of affected children (78), of whom 25% die from the initial rupture (79). AVMs are presumed to be congenital malformations, with only a small number found in association with genetic mutations such as hereditary hemorrhagic telangiectasia, which accounts for around 3% of all cases (79). Figure 25.15:Intraventricular hemorrhage. Coronal section of the brain showing extensive spontaneous intraventricular hemorrhage in a 6-year-old female, previously fit and well, who presented with sudden collapse. No structural cause for the hemorrhage was identified. (more...) Cavernous malformations (cavernoma) are formed from a compact mass of contiguous vessels with no intervening normal parenchyma, and may occur in the brain or spinal cord. They are rare, with an estimated prevalence of 0.4-0.5% in autopsy and MRI studies, and 50-80% are sporadic (80). Most cavernomas present in young adulthood, but some cases affect children. In childhood there is a bimodal age presentation, infancy through to 3 years and early puberty, 12-16 years (80). Aneurysm of the vein of Galen is very rare and often detected antenatally or in the early neonatal period, typically presenting with high-output cardiac failure, pulmonary hypertension or, in more severe cases, multi-organ failure. Management is with endovascular intervention which is timed according to physiological variables; however, sudden death may occur prior to diagnosis/ treatment and is usually associated with cardiac decompensation during an infective episode. Infants may develop hydrocephalus and seizures, whereas older children and adults may present with intracranial hemorrhage (81). Subarachnoid hemorrhage (SAH) is caused by ruptured intracranial (berry) aneurysms in 85% of cases across all ages, with the most common location being within the circle of Willis. Most aneurysmal SAHs are sporadic, but their discovery raises the possibility of underlying connective tissue disorders and polycystic renal disease. The 15% of cases that are non-aneurysmal may be associated with AVMs, Moyamoya syndrome (discussed below), arterial dissection, and coagulopathies (82). Arterial ischemic strokeAlthough rare in childhood, arterial ischemic stroke (AIS) has the same pathophysiology and evolution in children as in adults and the associated mortality is 7-28% (83). Around half of all affected individuals have predisposing conditions and some of the risk factors are shown in Table 25.2 (84). In contrast to adults, atherosclerosis is a very rare cause of childhood AIS. At least 10% of childhood cases remain idiopathic (83). Moyamoya disease is caused by progressive bilateral stenosis of the internal carotid arteries causing multiple AIS of variable ages, mostly affecting the anterior circulation. Collaterals develop from enlarged perforating vessels in the base of the brain which give a “puff of smoke” appearance on angiography, hence the Japanese term “moyamoya” (85). The etiology is unknown but it predominantly affects people of Asian origin. Moyamoya syndrome has the same pathological features but is associated with predisposing conditions such as neurofibromatosis type 1, Trisomy 21, sickle cell disease, and cranial irradiation, to name but a few (85). Sudden unexpected death in epilepsySudden unexpected death in epilepsy (SUDEP) is a well-known complication of any seizure disorder, with rates in childhood reported as 1.1-4.3/10,000 patient years (86). It is a diagnosis of exclusion after detailed post-mortem examination reveals no anatomical or toxicological cause of death in an individual with a known history of epilepsy. Structural brain lesions may be identified as the underlying cause of epilepsy, such as cortical malformations, hippocampal sclerosis, cerebral atrophy, and hydrocephalus, but often there is no obvious pathology identified. A number of mechanisms have been proposed, including cardiac arrhythmias and central apnea (86). Neurometabolic disordersNeurometabolic diseases are rare, but they account for a significant number of diseases that affect the pediatric brain and probably a significant proportion of neurodegenerative diseases in childhood (87). Approximately 25% of cases present during the neonatal period, often with acute encephalopathies which can be rapidly fatal. Older infants and children can present with slowly progressive symptoms, allowing time for investigation and diagnosis, and they are less likely to be encountered in the context of sudden unexpected death. Aminoacidopathies and organic acidemias can present within days of birth, due to postnatal accumulation of toxic metabolites which in utero would have crossed the placenta to be metabolized by the mother. Lysosomal and Peroxisomal storage disorders result in intracellular accumulation of macromolecules, often causing slowly progressive symptoms; the exception is Zellweger syndrome, which typically presents in the neonatal period with failure to thrive and neurological signs leading to early death. Neurotransmitter diseases present early with severe encephalopathy and drug-resistant seizures; these often involve monoamine synthesis and gamma-Aminobutyric acid (GABA) metabolism pathways (88). Occult CNS tumorsThese are extremely rare causes of sudden death in childhood. Various neoplasms have been described including aggressive tumors such as medulloblastoma (89-91) and glioblastoma (92), as well as tumors regarded as indolent such as pilocytic astrocytoma (90, 91). In such cases there may be vague preceding symptoms or the child may present acutely with sudden onset of severe headache or collapse just prior to death. Death may be due to mass effect or intra-tumoral hemorrhage leading to cerebral edema and raised intracranial pressure with herniation, leading to compression of vital cardiorespiratory centers. Intra-abdominal Causes of Sudden DeathGastroenteritisUsually there is a preceding history of diarrheal/vomiting illness, but sudden death may occur, presumably due to severe dehydration and serum electrolyte disturbance, with younger children and infants particularly at risk. Autopsy examination may reveal non-specific signs of dehydration, including sunken eyes and sunken fontanelles in infants, although these can be difficult to assess post-mortem. Stool cultures and virology may reveal the causative etiology. Gastrointestinal bleedingUpper gastrointestional (GI) bleeds cause hematemesis with subsequent melena, and any delay in treatment may rapidly lead to hypovolemic shock and death. Depending on the cause, the bleeding point may be found in the esophagus, stomach, or duodenum. Gastro-esophageal varices develop secondary to portal hypertension from any cause (e.g. portal vein thrombosis or cirrhosis with bleeding being the most serious complication (93)). Spontaneous rupture of the esophagus (Boerhaave syndrome) is very rare in children, with few cases reported in the literature (94). It is associated with intractable vomiting and may occur on the background of gastroesophageal reflux disease, as in Figure 25.16. Figure 25.16:Ruptured esophagus in a 13-year-old female with cerebral palsy and gastroesophageal reflux disease, found unresponsive after a three-day history of cough and fever. (From the autopsy archives at Great Ormond Street Hospital.). Gastric and duodenal ulcers, although uncommon in children, are most frequently caused by Helicobacter pylori infection but are also associated with chronic use of non-steroidal anti-inflammatory drugs (NSAIDs). Deep ulcers may erode through the stomach or duodenal wall causing death due to peritonitis, or through local arteries resulting in massive hemorrhage. Lower GI bleeds may cause hematochezia (fresh blood in the stool) or melena. Massive bleeds may rapidly lead to death if untreated. Intussusception is probably the commonest cause of GI bleeding in infants. It occurs when the proximal intestine telescopes into the more distal part, most frequently involving the terminal ileum. The lead point may be due to lymphoid hyperplasia in response to viral infection, such as Adenovirus or Rotavirus, or may occur as a complication of a Meckel’s diverticulum, intestinal duplication cyst, or, rarely, a neoplasm. Meckel’s diverticulum is the commonest congenital anomaly of the intestine and is due to incomplete obliteration of the vitelline (omphalomesenteric) duct during fetal life. Located in the distal small intestine, proximal to the ileocecal valve, it can cause life-threatening hemorrhage when ectopic gastric mucosa is present. Although a common cause of lower GI bleeding in the <2-year-olds, symptoms may present at any age. PeritonitisAcute appendicitis may occur at any age. Although uncommon in infancy it may be difficult to diagnose in life; the same is also true for older children with communication difficulties such as those with cerebral palsy or severe autism. Late presentation and or diagnosis may result in perforation, acute peritonitis, and death (Figure 25.17). Figure 25.17:Ruptured appendix. Peritonitis secondary to a ruptured appendix abscess in a 4-year-old female with attention deficit disorder. (From the autopsy archives at Great Ormond Street Hospital.). Intestinal obstructionVolvulus is the twisting of the gut around its mesentery, causing infarction and rapidly leading to death if untreated. It may occur at any age but classically presents in infancy. It usually occurs in the context of malrotation of the intestines during fetal life. This results in abnormal positioning and fixation of the intestines and principally involves the midgut. Mesenteric defects are a rare cause of intestinal obstruction from internal herniation of the ileum, and may be acquired or congenital. Acquired defects are due to traumatic injury or previous intra-abdominal surgery in which the mesentery has been incised and incompletely closed. Congenital defects are rare and their cause is unknown (95); typically, they occur near the terminal ileum and are round to oval with a diameter of 2-10 cm. They remain asymptomatic until herniation occurs; this may be intermittent, making ante-mortem diagnosis difficult. Hirschsprung’s disease is commonly diagnosed in the neonatal period with bowel obstruction and failure to pass meconium, or it can present later in childhood with chronic constipation. It is caused by failure of migration of neural crest cells within the colon leading to aganglionosis, and may involve the rectum and distal colon or may affect the entire colon. Life-threatening complications associated with bowel obstruction include perforation and enterocolitis. Another rare association is Ondine’s curse, which is a central hypoventilation syndrome which has been implicated in sudden death (96). Such disorders rarely present with sudden death in contemporary practice. Disorders of MetabolismMetabolic disorders may be congenital (inborn errors of metabolism/inherited metabolic diseases) or acquired, such as diabetes mellitus or vitamin D deficiency (due to poor diet and lack of sunlight). Metabolic defects all have the potential to cause sudden unexpected death. Often it is the age at presentation, together with the medical history and events leading up to death, that raise the suspicion for metabolic disease. At present, in the UK, six inherited metabolic diseases are screened for after birth as part of the neonatal Blood Spot (Guthrie) test, which involves taking a small blood sample via a heel prick within the first few days of life (97). These include phenylketonuria (PKU), medium chain acyl CoA dehydrogenase deficiency (MCADD), maple syrup urine disease (MSUD), isovaleric acidemia (IVA), glutaric aciduria type 1 (GA1), and homocystinuria, pyridoxine unresponsive (HCU). All are rare, with PKU and MCADD affecting around 1 in 10,000 babies born in UK and the others occurring in 1 in 100,000-150,000 live births; but all are amenable to treatment by dietary modification or supplementation and/or drug treatment (97). However, the list of other known metabolic diseases is legion and new diagnoses are constantly being added. Metabolic disorders were first identified as a possible cause of sudden unexpected death in the pediatric population in the mid-1980s. Subsequently, a range of suitable specimens to be taken prospectively as part of the autopsy were recommended which could be stored frozen for further investigation if required (98). For suspected inherited metabolic disorders, bodily fluid samples include urine, blood, bile, vitreous fluid, and CSF. (It should be noted that for metabolic investigation it is advisable to obtain samples as soon as possible after death to avoid interpretive difficulties as a consequence of post-mortem change.) Blood and bile spots can be stored on a Guthrie card but urine, vitreous, and CSF require freezing at -80 °C. A sample of skin, taken under sterile conditions, for fibroblast culture also requires freezing; fibroblasts will often grow from skin taken after a child has been dead for several days and are used for many enzyme assays. Macroscopic autopsy findings that raise the possibility of a metabolic disorder include dysmorphic features, a pale and enlarged liver, hypertrophic or dilated cardiomyopathy, and cerebral edema. Histological findings include severe fatty change in the liver, heart, skeletal muscle, or kidney, with identification aided by staining frozen tissue samples with oil red-O or osmium. Electron microscopy is a very useful adjunct to identify certain pathologies, such as multicore myopathy in skeletal muscle. Mitochondrial fatty acid oxidation (FAO) disorders are amongst the most common inborn errors of metabolism affecting infants and children (99) and may mimic SIDS. Fatty acid oxidation is essential for energy production and homeostasis, especially during periods of fasting. Fatty acids are metabolized in the liver, cardiac, and skeletal muscles by mitochondria, and the process involves numerous enzymes, co-enzymes, and transporters. Normally, partial oxidation of fatty acids in the liver produces ketones which are used as an alternative energy substrate to glucose, and metabolic intermediates of FAO are used for gluconeogenesis to maintain homeostasis during periods of fasting (100). Defects in any of the involved enzymes, co-enzymes, or transporters are responsible for the development of FAO disorders which ultimately prevent the effective use of fat during times of stress: when fasting or exercising, during cold temperatures, or when there is increased metabolic demand due to illness. Metabolic decompensation results in acidosis, hypoglycemia, coma, and rapid deterioration to death. Inheritance of FAO disorders is in an autosomal recessive manner, with the age at presentation dependent on the particular enzyme/transporter involved (6). Detailed description of individual FAO disorders is beyond the scope of this chapter; however, some of the defects associated with sudden death in infancy and childhood are listed in Table 25.3. Table 25.3:Fatty acid oxidation disorders. (Adapted from (100). Persistent hyperinsulinemic hypoglycemia of infancy (PHHI, “nesidioblastosis”) is a rare genetic disorder thought to affect 1 in 50,000 births but with increased incidence in communities where there is a high level of consanguineous marriage (103). Neonates may present with seizures, somnolence, and motor abnormalities and there may be macrosomia or hypertrophic cardiomyopathy (104). There is a high risk of brain damage and death. First-line treatment is with diazoxide, but this is ineffective in some forms, in which octreotide may be used. Many mutations have been identified, but the commonest and most severe monogenic form is caused by mutations of the subunits of the beta-cell plasma membrane K+ ATP channels, leading to focal islet cell adenomatosis (104). Diagnosis in life depends on a high index of suspicion, and pre-operative 18Fluoro-DOPA-PET scans are used to localize lesions prior to surgery. In some cases of diffuse disease, total pancreatectomy may be required. Diagnosis at autopsy can be difficult and depends on adequate examination and sampling of the pancreas. Different morphological types are identified at microscopy including focal adenomatosis/adenomatous hyperplasia and diffuse PHHI in which careful analysis of morphology of islet of Langerhans reveals large B cells with abnormally large, hyperchromatic nuclei (103). Immunohistochemistry with a cocktail of pancreatic enzymes is helpful to highlight overactive cells. Genetic testing of suspected cases and family counseling is essential. Type 1 diabetes mellitus (T1DM) is caused by failure of the endocrine pancreas to produce insulin. If poorly controlled, and especially during inter-current illness (usually infection), diabetic ketoacidosis may ensue. Ketoacidosis results from high concentrations of ketone bodies formed by the breakdown of fatty acids and amino acids which are used as an alternative energy source in the absence of utilizable glucose (insulin is essential for the cellular uptake of glucose from the blood). Without prompt treatment, ketoacidosis rapidly leads to coma and death, but even with treatment there remains a significant risk of cerebral edema, usually between 4 to 12 hours of initiation (105). “Dead in bed syndrome” is a poorly understood cause of sudden unexpected death in T1DM, the cause of which is unknown but has been postulated to be associated with cardiac arrhythmia (106). Bacterial InfectionsSepsis and septic shockSepsis is defined as a systemic inflammatory response (SIRS) in the presence of invasive infection. Severe sepsis requires cardiovascular dysfunction or acute respiratory distress syndrome or dysfunction in two or more other organs (107). Septic shock is a subset of sepsis with cardiovascular dysfunction and is associated with a greater risk of mortality than sepsis alone. In pediatric sepsis a wide variety of organisms have been implicated including Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meninigitis, Hemophilus influenza, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella sp., some of which will be described in more detail below. Viral pathogens may also manifest as severe sepsis or septic shock including RSV, Influenza, Parainfluenza, and Adenovirus, although the mortality is usually less than with bacterial infection. Diagnosis of sepsis as the cause of death can be difficult at autopsy, especially when a clear macroscopic or histological focus of infection cannot be identified. The clinical history may, or may not, be helpful, as often children are reported to be “snuffly” or as having signs or symptoms which suggest mild infection. In all cases of sudden unexpected death, microbiology samples from “sterile sites” are taken routinely as part of the autopsy protocol. This is regardless of any history of clinical signs or symptoms leading up to the death, as children, especially infants, may exhibit no or very non-specific signs of infection prior to death. Before opening the cadaver, and with particular care to optimize sterility, cerebrospinal fluid (CSF) and other samples such as nasopharyngeal or rectal swabs may be obtained for virology and bacteriology. On opening the thorax, blood cultures can be obtained from the internal jugular vein or right ventricle and tissue samples/swabs from the lung and spleen for bacteriology, again using a sterile technique. Tissue samples/swabs for virology include heart, lung, spleen, bowel, and, in some cases, brain. Additional fluids which may also be collected for microbiology studies include urine, pleural, pericardial, and peritoneal fluid if applicable. There are various signs which may be identified at autopsy which raise the possibility, but are not pathognomic, of sepsis. A generalized hemorrhagic/purpuric rash may be present as a consequence of disseminated intravascular coagulation. Bilateral adrenal hemorrhages are often striking in appearance, with both adrenal glands appearing enlarged and almost black in color; this finding is classically associated with the Waterhouse-Friderichsen syndrome secondary to fulminant meningococcal disease but may be present in sepsis from any cause. However, non-sepsis-related causes are also described, including coagulopathies, hypotension, and any cause of physiological stress (108). It is quite obvious that if a clear focus of infection is identified on macroscopic examination — for example, empyema or purulent meningitis (Figure 25.12) — this helps in establishing an accurate cause of death. If no focus of infection is identified macroscopically or on histological examination of tissue, but microbiology cultures from three separate sites grow a recognized pathogen in pure culture, this is generally accepted to be causative of death. However, it should be emphasized that difficulties in the interpretation of the significance of post-mortem microbiological results persist, especially when multiple organisms are present which may be due to “post-mortem translocation” often of “gut-type flora”. Post-mortem translocation or overgrowth is a difficult concept, however, because it is not universal and does not appear to be clearly dependent on post-mortem interval. Toxic shock syndrome (TSS) is a severe and potentially fatal condition, typically caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes. The toxins act as super-antigens by bypassing the usual antigen presentation pathway; they cause massive T-cell activation with an uncontrolled release of inflammatory mediators (109) and resultant massive vasodilation, capillary leak, and hypotension (toxic shock). It has been associated with tampon use (110), burns, and secondary bacterial infection in chicken pox. In the UK the incidence in children is reported to be 0.38 per 100,000 and mortality estimated at 28% (109). Clinical manifestations may include pharyngitis or skin infections with progression to fever, generalized maculopapular rash with desquamation, profound hypotension, and multi-organ failure (111), but onset may be abrupt, making diagnosis challenging early on. Many streptococci and staphylococci contain the genes for toxin production, and molecular subtyping allows for identification of the presence of these genes. However, despite having the gene, toxins will only be expressed under certain conditions, and most people develop immunity to these “super-antigens early in life” (110). Streptococcal TSS has been shown to affect younger children more commonly than staphylococcal TSS (109). Neisseria meningitidis (meningococcus) is the leading cause of infection-related death in early childhood (112), with a mortality rate of >20% in children with meningococcal sepsis (70). Meningococcus is a gram-negative diplococcus of which there are 12 serogroups, with most invasive diseases caused by groups A, B, C, W, X, and Y, of which groups B and C are the major disease-causing strains in the UK (112). There is a bimodal age distribution, with most cases occurring during the first year of life and in adolescence. Rare cases occur in the neonatal period (<28 days old) (113). Meningococci are normally carried in the nasopharynx of healthy individuals, with disease occurring when bacteria are transmitted to susceptible individuals and outbreaks ensuing when large groups of young people come together, such as at the start of university semester. Clinical presentation of meningococcal disease is with septicemia or meningitis or as a combination of the two (114); however, rapid onset means that sudden death may occur before any clinical diagnosis is established. In such cases there may only be subtle findings at autopsy rather than the classic signs of meningococcal septicemia described above. Tissue and fluid samples may be sterile if the individual has received antibiotics ante-mortem, and PCR analysis may be required to confirm the diagnosis; results from ante-mortem blood and CSF cultures should be actively sought. Atypical presentations such as septic arthritis, pneumonia, epiglottitis, and endocarditis are well described for the less common meningococcal capsular groups, W and Y, and mainly occur in adults. However, rare cases of adolescents presenting with primarily gastrointestinal symptoms leading rapidly to death have been recently reported in the UK associated with a hypervirulent group W strain; all had multi-organ failure, with one case noted at autopsy to have necrosis of the intestines (115). Hemophilus influenzae is a gram-negative anaerobic coccobacillus that can cause severe infection in infants and children <5 years. Some strains have a polysaccharide capsule and are identified on the basis of antigenic properties (serotypes a-f), of which type b (Hib) is the most pathogenic (116). Unencapsulated or non-type-able (NTHi) strains also exist which are more susceptible to complement mediated bacteriolysis and phagocytosis, rendering them less common causes of invasive infection (116). H influenza causes diseases ranging from non-invasive otitis media to severe infections such as pneumonia, meningitis, epiglottitis, septic arthritis, and septicemia (117). Since the introduction of routine vaccination of infants against type b (Hib), there has been a decline in the incidence of Hib-related disease. However, emerging reports indicate an increase in invasive non-Hib infections worldwide, including Hia, Hif, and NTHi (117). Non-Hib infections are reported to be similar, although less severe than those reported with Hib. As always the most vulnerable individuals at the extremes of the age spectrum are likely to be more severely affected. Neonatal NTHi disease is more commonly associated with prematurity and early onset infection (<48 hours) (118). Streptococcus infections cause a wide variety of disease in childhood. Streptococcus pneumoniae (pneumococcus) is the leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide (114). Group A streptococcus (GAS/Streptococcus pyogenes) may cause mild focal infections to severe life-threatening disease or invasive GAS, which has a fatality rate of 7-25% (119). Invasive GAS commonly occurs via an initial skin infection and is well known as a cause of bacterial superinfection during concurrent chicken pox and is also associated with burns. It causes one of three clinical manifestations: septicemia, necrotizing fasciitis, or TSS. Virulent strains of GAS, including M1, 3, 12 and 28, are associated with TSS. Group B streptocococcus (GBS) is part of normal gut and genital tract flora in 20-40% of women. Maternal colonization may lead to severe neonatal infection and early neonatal death. GBS was previously thought to be the most common cause of bacteremia in febrile infants <90 days of age, but recent data have suggested that it may be superseded by Escherichia coli (114). Although rare in infants more than 3 months old, so-called late, late-onset GBS infection (defined as GBS infection in infants >90 days old) is well recognized and is associated with a mortality rate of 20%; at autopsy there may be bacteremia without histological evidence of infection (120). The most virulent serotypes are capsular types Ia, Ib, II, III, and V (121). Staphylococcus species cause a range of disease in children from mild skin infections to severe sepsis. The most important is Staphylococcus aureus which, if causing a bacteremia, has a mortality rate of 15-25% (122). Complications include infective endocarditis, CNS embolism, septic arthritis, and empyema. Staphylococcal scalded skin syndrome (SSSS) is a potentially life-threatening disease caused by a phage group II Staphylococcus aureus infection. More common in children <5 years, it appears abruptly with diffuse erythema and fever; there follows widespread epidermal damage with vesiculobullae and desquamation. Exfoliation of the superficial epidermis occurs at the stratum granulosum due to the effects of circulating bacterial exotoxin acting on desmoglein 1 (123). Potentially fatal complications include secondary infection, pneumonia, and sepsis, but despite this, mortality is less than 10% compared to 40-63% in adults (123). Panton-Valentine leucocidin (PVL) is an important toxin expressed by <2% of clinical isolates of Staphylococcus aureus, both methicillin-resistant (MRSA) and methicillin-susceptible strains (124). PVL-expressing strains have been associated with fatal necrotizing pneumonia in young children (125), as well as necrotizing fasciitis, purpura fulminans, and Waterhouse-Friderichsen syndrome (126). PVL proteins have two major actions which cause severe disease in humans: direct effects on white blood cells cause pore formation in the cell membrane, resulting in leakage of intracellular contents with subsequent apoptosis and local tissue necrosis facilitating multiplication of bacteria (127). PVL proteins can also act as super-antigens eliciting a massive immune response, leading to a toxic-shock type picture. Staphylococcus aureus is responsible for 70-90% of pediatric osteomyelitis, which is a relatively common condition. PVL-associated cases are much more severe — often involving multiple bones, and sometimes complicated by infective endocarditis, necrotizing pneumonia, cerebral infarcts, rhabdomyolysis, and septic shock and death (127). Citrobacter koseri (formerly Citrobacter diversus) is a facultative anaerobic, gram-negative bacillus found in the intestinal tract of humans and animals and also present in soil and water (128). It is recognized as a potential but rare pathogen in infancy and childhood, causing meningitis with concurrent cerebral abscess in 75% of cases (128). The mortality rate is greater than 30% and those who survive are at high risk of severe neurological sequelae (129). The risk of disease is highest in the immunosuppressed and in children with cyanotic congenital heart disease. Other predisposing factors include neurosurgery, middle ear and sinus infections, poor dental hygiene, and congenital lesions of the head and neck. In neonates, early onset infection suggests vertical transmission during delivery; late onset infections also occur and nosocomial outbreak due to umbilical colonization has been reported. Salmonella sp. are the cause of commonly encountered infections manifesting as gastroenteritis and septicemia. Children may develop multisystem infection such as osteomyelitis, liver and splenic abscesses, and overwhelming sepsis, which may be fatal. Children with sickle cell disease are more susceptible to infection. ConclusionsNatural causes of sudden unexpected death in infants and children are myriad, and this chapter provides an overview of the most common and/or important entities. The requirement for thorough autopsy by a specialist pediatric pathologist is highlighted by the vast range of conditions that may be encountered, many of which are either unique to this demographic or present with unusual features. In some circumstances, particularly unusual CNS or cardiovascular-related deaths, further super-specialist input may be required and there should be a low threshold for discussion and/or referral to a pediatric neuropathologist or cardiac pathologist. Furthermore, the importance of ancillary investigations is highlighted, including full histological evaluation and the obtaining of appropriate tissue samples for further investigations, such as in cases of suspected metabolic disorders. Given that unexplained deaths represent a significant proportion of sudden unexpected deaths in infancy and childhood (albeit to a lesser extent in childhood), these have important public health and research implications, since these categories are essentially diagnoses of exclusion. This further emphasizes the importance of appropriate specialist pediatric autopsy examination. References1.Wang H, Liddell CA, Coates MM, Mooney MD, Levitz CE, Schumacher AE, et al. Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9947):957-79. https://doi.org/10.1016/S0140-6736(14)60497-9. 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[PubMed: 19192951] 127.128.129.What are the leading causes of death in children ages 1 to 4 and ages 4 to 15 years?In 2019, unintentional injuries (accidents) were the leading cause of death for children ages 1–4 (7 per 100,000) and ages 5–14 (4 per 100,000). Among children ages 1–4, birth defects, cancer, and homicide also were leading causes of death.
What is the death of a child under one year of age?Infant mortality is the death of young children under the age of 1. This death toll is measured by the infant mortality rate (IMR), which is the probability of deaths of children under one year of age per 1000 live births.
Which are the leading causes of accidental death in infants under 1 year of age quizlet?Airway obstruction injury (suffocation) is the leading cause of unintentional injury-related death among infants under age 1.
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