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Molecular analyses of sudden infant death syndrome (SIDS) autopsy material turned up evidence of neuroinflammation, with a specific virus identified in one case, researchers reported.

Among 64 SIDS cases and 15 controls with measurement of cerebrospinal fluid (CSF) levels of neopterin from activated macrophages, a total of six SIDS cases with high CSF neopterin were identified, "suggestive of neuroinflammation," reported Robin Haynes, PhD, of Boston Children's Hospital, and colleagues.

Metagenomic next-generation sequencing (mNGS) detected changes associated with human parechovirus type 3 (HPeV3) infection in tissue and CSF from one of the six SIDS cases with elevated neopterin, they .

In this one SIDS case, HPeV3 turned up in the CSF (range 1.1-23.6 reads per million), hippocampus (0.1-0.3 reads per million), brainstem tissue (0.1-1 reads per million), and liver (794 reads per million).

Additionally, single-nucleus RNA sequencing (snRNAseq) of HPeV3-positive medulla tissue in the brainstem revealed "dramatic enrichment" of transcripts for genes with predominately inflammatory functions when compared with three age-matched SIDS cases with normal CSF neopterin levels.

Interruption of the brainstem's vital respiratory center activity could lead to lack of respiratory drive and cause death in sleep.

"We postulate that the HPeV3-positive SIDS case represents a proof of principle of viral-mediated medullary changes that potentially contribute to pathogenesis in some sudden and unexpected deaths yet go unrecognized using standard autopsy techniques," Haynes and colleagues wrote.

"It remains unknown whether this infant died of HPeV3 or whether the medullary changes associated with infection contributed to pathogenic mechanism of SIDS," they added. "This case, however, reinforces the need to apply modern techniques as part of the 'molecular autopsy' in sudden death in pediatrics."

The infant identified as having HPeV3-positive SIDS was an 11-day-old girl, who was born full-term with no complications. She had presented to the emergency department with fussiness, poor feeding, and fever, Haynes and colleagues noted.

Upon the infant's discharge, her mother fell asleep with her on the couch. Hours later, the mother found the infant not breathing. Resuscitation efforts were unsuccessful.

Overall, autopsy findings suggested a normally developing infant with no injuries. Microbiologic, toxicologic, metabolic, and vitreous fluid chemistry results were normal.

The cause of death was listed as "sudden infant death while bedsharing," and the manner of death was stated as "undetermined."

However, after molecular analyses, a total of 99% of the HPeV3 genome was assembled, and phylogenetic analysis revealed clustering with cases from a 2014 outbreak in Missouri and Kansas, Haynes and colleagues reported.

"We were surprised about the extent of molecular changes in the cells within the lower brainstem (medulla) associated with the HPeV3 viral infection, especially considering the relatively minor symptoms that are described in this report," Haynes told MedPage Today in an email. "Using the molecular approach of single nuclei RNAseq, we were able to see in a cell-specific manner how different cells of the medulla were affected."

"Our laboratory and others have shown abnormalities in the medulla of SIDS infants before," Haynes added. "Minor infection prior to death is also associated with SIDS. This report provides evidence supporting a mechanistic link between infection and brainstem abnormalities in SIDS."

At the same time, mNGS in the other five SIDS cases with elevated CSF neopterin level that Haynes and colleagues examined showed no evidence of pathogenic species in tested tissues.

In these five cases, "the cause of neuroinflammation remains unknown," Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, wrote in an accompanying the study in JAMA Neurology.

"It is possible that viral infection or viral antigen may be driving the inflammation," Nath noted. "mNGS may not be sensitive enough to identify the pathogen if it is present in low copy numbers. Another possibility is that the virus may have initiated the process but may have been cleared by the time of death while the inflammation may persist. Yet another possibility is that although the viral genome may have been cleared, viral antigen can persist for extended periods, driving the inflammation. In such cases, mNGS would not be able to identify the pathogen, and antibody-based techniques may be helpful."

Ultimately, "this study indicates that a thorough investigation of SIDS is needed, which should also include signs of neuroinflammation and deep sequencing for pathogen discovery," Nath concluded.

For their study, Haynes and colleagues screened postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 for elevated inflammatory markers.

Tissue from SIDS cases with elevated CSF neopterin underwent mNGS to look for infectious pathogens. And, brainstem tissue from a subset of these cases was analyzed by snRNAseq to measure cell type-specific gene expression associated with neuroinflammation and infection.

Analyses were performed from April 2019 to January 2023.

Low sample size, due to rarity of death and autopsies in infants, "was a necessary limitation of the study," Haynes and colleagues noted.

Limitations also included that the research team did not perform HPeV3 culture as a criterion standard confirmatory assay of infection.

"In the context of sudden and unexpected death, our study suggests that different methodological approaches are necessary to fully understand the scope of the pathology in these cases, including cases in which environmental factors such as unsafe sleep may play a role," Haynes said.

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