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Bundock EA, Corey TS, Andrew TA, et al., editors. Unexplained Pediatric Deaths: Investigation, Certification, and Family Needs [Internet]. San Diego (CA): Academic Forensic Pathology International; 2019.
JACOB
“Jacob (on right) exuded such a contagious joy that his smile could make any day bright. He and his twin brother were 27 months old at the time of Jacob’s sleep-related sudden death. It is still so hard to believe. Watching his brother grow up without him by his side is a painful reality of our loss. Not knowing why Jacob is not with us makes it worse. Remembering him and keeping his memory alive is our way of honoring him. Learning as much as we can from his death is so important to us. We don’t want this to happen to any more families.”
– Jacob’s Mom and Dad
OUTLINE.
The focus of this chapter is the role of microorganisms and infectious disease processes in causing or contributing to sudden, unexpected pediatric deaths. Among some of the challenges in examining the role of infectious disease in these cases is interpreting postmortem laboratory results; for example, what constitutes contamination and what is an infection of significance? What are the factors that allow for this determination? Another matter of concern is how and when is a death attributed to infection as opposed to a death occurring with an infection? What studies may be undertaken to pursue the investigation and how best can we use the expertise of clinical pathologists in this regard? It is also important to consider postmortem specimen collection: What is appropriate in all situations? Is there a recommended minimum standard based on medical evidence? What is appropriate for different age groups? Lastly, this chapter will review the current state of knowledge regarding the relationship between vaccinations and sudden death in infancy and the renewed research interest in the role of microorganisms in sudden unexplained infant deaths.
In a 2017 publication, Murphy et al. presented final 2015 data on US deaths, death rates, life expectancy, trends, and childhood mortality (23 455 infants and 9376 children ages 1–14 years). No specific trends with respect to infection and infants or children were identified. Infants aged 12 months and younger demonstrated higher rates of death from septicemia and respiratory infections than in older pediatric age groups (1). Based on data from death certificates, death rates (see Table 6.1) and raw numbers of deaths (see Table 6.2) were reported as a function of age and cause/mechanism of death. Across the age groups, deaths from septicemia and respiratory infections were most common; whereas, death from Clostridium difficile enterocolitis, HIV and viral hepatitis were relatively uncommon (see Table 6.2).
Childhood Death Rates, 2015 US Mortality Data (1).
Childhood Deaths, 2015 US Mortality Data (1).
With respect to deaths of infants due to infectious causes, the following infections were reported from most to least common (see Table 6.3): bacterial sepsis of newborn; gastroenteritis; septicemia; influenza and pneumonia; meningitis; acute bronchitis and bronchiolitis; bronchitis, chronic and unspecified; acute upper respiratory infection; certain intestinal infectious diseases; candidiasis; whooping cough; meningococcal infection; HIV; congenital syphilis.
Infant Deaths Due to Infectious Diseases, 2015 US Mortality Data (1).
A search of the medical literature from the years 2008 through 2018 finds case reports of sudden unexpected deaths in pediatric cases with the most numerous reported cases for viral infections, including human herpesvirus 6 (HSV-6), Epstein–Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (1–4), coxsackie virus A16 (5), respiratory syncytial virus (RSV) (6), influenza B virus (7), Ljungan virus (Perechovirus) (8), and dengue virus (9). There are also multiple reports of infectious heart diseases in the pediatric population associated with sudden death; these include pancarditis due to concomitant infection with enterovirus, varicella-zoster virus, and EBV (10); myocarditis from CMV (11) and coxsackie B3 (12); and infectious endocarditis from enterococcus (13), pyogenic bacterial infection (14) and lactococcal infection (15). Of note are case reports of sudden death from hand, foot, and mouth disease (16), tonsillitis (17), CMV pneumonia (11), respiratory diphtheria (18), asymptomatic acute laryngotracheobronchitis (19), previously undiagnosed rheumatic heart disease (20), and tuberculous meningitis (21).
Postmortem cultures have been part of autopsy practice for over one hundred years, but their value has been in contention the entire time (22–24). Some investigation into the validity of postmortem bacterial cultures predates the antibiotic era. Morris reports that in 1916, Fredette obtained blood cultures from 116 decedents within 30 minutes of death yet had only a 9% rate of identifying a single bacterial organism in monoculture (25). This rate accords with many other studies over the past century that demonstrate cultures determine the cause of death in about 5% to 10% of autopsies (15, 22, 25–27).
A 2010 study by Weber on viral testing in cases of sudden unexpected death in infancy included immunofluorescence assays, cell cultures, and polymerase chain reaction (PCR). Viral infection (as indicated by positive viral cultures) was a cause of death in 4% of cases, and viral infection contributed to the cause of death in less than 2% (28).
A review of past literature indicates that particular bacterial culture results are more likely indicative of death by infectious disease in sudden unexpected death in childhood. Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and the fungus Candida albicans were of concern in papers published in the 1960s; later, postmortem bacterial cultures of Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria spp., Haemophilus influenzae, and intestinal bacteria including Bacteroides fragilis and Enterobacter spp., were added to the list of infectious agents grown in postmortem cultures causing pediatric death. However, to confound matters, more recent studies demonstrate that these same microorganisms may grow in culture from postmortem blood in noninfectious deaths (22, 25), thereby creating a challenge in interpretation of the significance of any postmortem bacterial culture.
Two pieces of conventional wisdom in the practice of autopsy pathology are contradicted by some scientific investigations. Conventional wisdom holds that in the absence of histologic evidence of infection, growth of a bacterium in culture must be a contaminant and that bacterial contaminants increase with time in refrigerated bodies. However, studies have demonstrated the contrary in both regards (22). First of all, histologic evidence of infection may be missed during routine autopsy sampling; case in point, Morris states that Adelson and Kinney’s 1956 study found no relationship between blood culture results and histologic findings. Second, in 1958, Kurtin (reviewed in Morris [25]) showed no increase in bacterial culture contaminants between 6 and 48 hours after death, and in 2009, Saegeman (reviewed in Riedel [22]) found that bacterial contaminants peaked in the first five hours after death. In 2011, Pryce and colleagues compared immediate postmortem samples from the emergency department to postmortem cultures drawn at the time of autopsy in 136 sudden unexpected deaths in infancy. They found that only 27% of the cases grew bacterial cultures from the autopsy samples after the same cases had samples drawn immediately at the time of death which had no growth, at a mean postmortem interval of 4.2 days (29). In 2013, Tuomisto et al., using combined PCR and bacterial cultures, obtained satisfactory results with cultures obtained between one and seven days postmortem (mean, 2.4 days); they found that blood rapidly developed contaminants, but pericardial fluid and liver provided the most sterile samples up to five days after death (30). In bodies refrigerated before putrefaction sets in, it is still unclear what the ideal upper limit is (in days after death) for collection of bacterial cultures. The literature does not provide a clearly delineated point at which cultures become unreliable due to postmortem bacterial contamination and overgrowth. Some authors maintain that interpretation of bacterial cultures may be challenging with any postmortem interval and therefore may require consultation with a pediatric microbiologist (28). Finally, it must be remembered that the postmortem interval cannot be precisely determined in an unwitnessed death, therefore, conditions affecting postmortem changes, such as body temperature at the time of death, ambient temperature, and cooling rate of the body, are mostly unknown.
Confidence in interpretation of culture results depends upon reliable culture results. Good technique in collecting samples is necessary for obtaining the best culture results — that is, a culture free of contaminants — but there is no single technique which prevents all contaminants. In the 1960s, O’Toole and colleagues showed that even operating room-level sterile technique resulted in about half of postmortem cultures growing bacterial contaminants (31). Proposed mechanisms by which postmortem contamination occurred in such a study design included agonal spread within the body of the decedent and postmortem translocation of bacteria. Agonal spread is theorized to be due to the gaping of endothelial cells in ischemic vessels during the last minutes of life; however, this hypothesis has not been supported by the literature. Postmortem translocation as a theory of postmortem contamination is much better supported by studies but is not always explanatory of culture results (22). For example, antemortem episodes of bacteremia may result in positive autopsy blood cultures without contributing to death. Additionally, Morris, reviewing Harrison’s studies, found that live infants who slept prone had more coliforms and other Gram-negative bacilli in nasal swabs obtained early in the morning than either those infants who slept supine or prone-sleeping infants who were swabbed later in the day; the organisms may have grown overnight in secretions pooling in the upper airways during prone sleep (25). Indeed, such positioning could contaminate normally sterile sites such as the lungs (32). Morris also makes the point that isolates of Staphylococcus aureus, coliforms, and group B streptococcus from upper airways in sudden unexpected infant deaths should not be attributed to postmortem artifact but are not certainly causal to death (25).
Two points of agreement arise from numerous contributions to the literature:
All in all, the best practice remains to interpret culture results in conjunction with clinical presentation and anatomic findings. In cases with equivocal culture results, consultation with a pediatric microbiologist is helpful. In cases in which it is clear from microscopy that an infectious process is apparent, but the causative microorganism is not evident from cultures, consultation with a state laboratory and/or with the Centers for Disease Control and Prevention may be beneficial.
Both clinical medicine and forensic pathology are moving beyond the standard of blood cultures to new technologies such as PCR identification (30, 33). In viral myocarditis, immunohistochemistry (IHC) and PCR are replacing viral cultures as methods of viral detection (34). Christoffersen found postmortem C-reactive protein corelated with death due to an infectious etiology in a majority of studied cases, although sample size was small (27). At present, cultures continue to be a requisite part in many autopsy investigations of sudden unexpected deaths in infancy and childhood, even though the diagnostic yield of these cultures is often low and their interpretation is sometimes difficult at best.
There is a temporal association of sudden unexpected infant death and vaccines, with the peak age of sudden unexpected infant death (age 1–4 months) coinciding with administration of multiple vaccines. In the 1970s, case reports of deaths occurring soon after diphtheria-pertussis-tetanus (DPT) vaccination raised concern that there was a causal link between vaccinations and sudden unexpected deaths in infancy (35). Of seven, large cohort and case-control studies that were conducted to evaluate this association, five found no relationship between DPT vaccination and subsequent sudden unexpected death in infancy (36) and two only found a temporal relationship in specific subgroup analysis (37). It has been hypothesized, but not proven, that vaccination could, in rare instances, trigger a lethal outcome in specific vulnerable babies, such as those with nervous system abnormalities (e.g., hypoplasia of the arcuate nucleus) or babies with cardiac ion channelopathies (38, 39).
Multiple analyses of the US Vaccine Adverse Event Reporting System (VAERS) database have been conducted and have consistently found no relationship between vaccines and sudden unexpected deaths in infancy (40). The decreasing trend of deaths after vaccination reported to the US Vaccine Adverse Event Reporting System (VAERS) database since the Back to Sleep campaign began in 1994 suggests that the association between sudden unexpected death in infancy and vaccination is coincidental rather than causal (41). Indeed, despite the increased number of vaccines over time, the rates of sudden unexpected death in infancy have declined. The Institute of Medicine, in 2003, concluded after a review of the literature of vaccines and sudden unexpected death in infancy that there was no causal relationship (42).
On the contrary, population-based case-control studies in several countries have consistently found vaccines to be protective against sudden unexpected death in infancy (43); this protective effect persists after controlling for potential confounding factors (demographic characteristics, infant medical history, and sleep environment). Further, a meta-analysis of four studies reported an adjusted odds ratio of 0.54 (95% CI, 0.39–0.76), i.e., immunization decreased the risk of sudden unexpected infant death by 46% (44). It has been theorized that vaccination with Diphtheria-Pertussis-Tetanus (DPT) and Haemophilus influenzae type b (HIB) may induce antibodies that cross-react with bacterial toxins implicated in sudden unexpected deaths in infancy (45). It has also been theorized that infants who are immunized may be healthier at the time of immunization (46), since infants with a current or recent illness may be more likely to have their vaccines deferred (44); infants with a recent illness have also been shown in some studies to be at higher risk for sudden unexpected death in infancy (47).
In recent years there has been renewed interest in examining the role of microorganisms in sudden unexplained deaths in infancy. Much of this interest has been sparked by studies of potential microbiome effects on hippocampal development and regulation in animal models (48). This line of inquiry aligns with the “Triple Risk Model” proposed by Filiano and Kinney in their 1992 publication (49), which suggested that sudden unexplained infant deaths were in part attributable to neurodevelopmental alterations resulting in impaired arousal mechanisms. A preliminary study pursuing the hypothetical link between microbiomes, neurodevelopment, and sudden unexplained infant deaths used both case samples and age-matched control samples screened by PCR assays targeting 16sRNA genes of various gut microorganisms (50). The results and conclusions of this study seemed to support the hypothesis; however, a subsequent study in 2017 by Leong, Goldwater et al. using more refined research methodologies and statistical analysis found no evidence of a link between changes in an infant’s intestinal bacterial flora and the incidence of sudden unexpected deaths in infancy (51). In short, the hypothesis that altered microbiome profiles in infants are at least in part responsible for sudden unexplained deaths has to date not been borne out.
In 2015 Fernandez-Rodriguez et al. published recommendations for postmortem collection of specimens for microbiology testing (52). The authors outline specific steps in best practices in collecting specimens at autopsy. They also provide a comprehensive guide pertinent to the pediatric population as to which specimens to collect and under which circumstances. While their recommendations are thorough, they are not necessarily reflective of what a forensic pathologist encounters at autopsy; for example, most infants die with an empty bladder and, therefore, urine is seldom available. Furthermore, some forensic pathologists practice in facilities which lack frozen tissue storage. In constructing our own recommendations (Table 6.4), we use the recommendations of Fernandez-Rodriguez as a guide while also keeping in mind the limited facility resources and case limitations encountered by many practicing forensic pathologists. Funding for improved facility resources is certainly an area which needs attention. It should be emphasized that although the microbiology laboratories used routinely by forensic pathologists may not perform molecular studies such as PCR, many state laboratories and the Centers for Disease Control and Prevention do perform these tests and at no cost to the submitter.
Procedural Guidance and Key Considerations for Infectious Disease Evaluation.
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