NEW YORK – New research suggests infection-related neuroinflammation may be behind at least some cases of sudden infant death syndrome (SIDS), leading to related gene expression changes in affected infants' brainstem tissue. The work appeared in JAMA Network Open on Monday.
"This report provides evidence, a proof-of-principle, supporting a mechanistic link between infection and brainstem abnormalities in infants dying suddenly and unexpectedly," senior and co-corresponding author Robin Haynes, a pathology researcher at Boston Children's Hospital, said in an email. She noted that the work "provides support for new, enhanced, molecular approaches to SIDS that can inform us of pathology beyond what is currently done to determine the cause of death."
Although SIDS has been linked to alterations in the medulla brainstem region, Haynes explained that at least some infants who died of SIDS have also shown signs of minor infection, prompting a more detailed search for potential pathogens.
For their study, Haynes and colleagues from Boston Children's, Harvard Medical School, and elsewhere used a range of molecular analytical methods to assess various tissue and other samples obtained from up to 71 SIDS cases and 20 unaffected controls. Using high-performance liquid chromatography, for example, they searched for the neuroinflammation-related immune biomarker neopterin in cerebrospinal fluid (CSF) samples from a subset of 64 SIDS cases and 15 controls.
The team also relied on multiplex fluorometric assays to characterize cytokine profiles in CSF and blood serum samples from a subset of cases and controls, and characterized potential pathogen patterns in liver, cerebrospinal, brain, and brainstem tissue samples with metagenomic sequencing.
"Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly," the study authors explained.
After uncovering higher-than-usual neopterin levels in CSF samples associated with half a dozen SIDS cases, pointing to potential neuroinflammation, the team went on to perform single-nucleus RNA sequencing on medulla brainstem tissue from one of these cases: a full-term infant who died at 11 days old after experiencing a brief fever and fussiness.
With metagenomic sequencing, the researchers found that that patient appeared to be infected with an RNA virus from the Picornaviridae family known as human parechovirus 3 (HPeV3). HPeV3 "is one of approximately 17 strains of the HPeVA species," they explained, noting that while HPeVs "typically cause mild childhood infections, severe HPeV3 can be accompanied by seizures, meningitis, white matter lesions, microglial activation, and reactive astrocytosis."
In the SIDS case marked by HPeV3, the team also saw enhanced expression of inflammation-related genes in brainstem samples, particularly in vascular cells — results that distinguished that SIDS case from three age-matched, noninflammatory SIDS cases and from one control CSF sample containing typical levels of neopterin.
"With HPeV3 infection increasingly recognized, results of this study support HPeV3 testing and new molecular tools in the examination of sudden and unexpected infant deaths," the researchers wrote, noting that SIDS remains a highly heterogeneous condition that also includes noninflammatory forms.
Likewise, they said, "[m]ore work is needed to understand if HPeV3-induced changes in the medulla, including on serotonergic neurons, underlie the autonomic dysregulation in HPeV3 infection or whether there are distinct immunologic phenotypes that correlate with death [versus] survivable manifestations of infection."
In a corresponding editorial in JAMA Network Open, Avindra Nath, director of the infections of the nervous system section at the US National Institute of Neurological Disorders and Stroke, noted that the neuroinflammation source has not yet been reported for five of the SIDS cases profiled, suggesting additional analyses may be needed to uncover low-level infections or immune system effects involving still other pathogens.
Still, Nath suggested, the new study "indicates that a thorough investigation of SIDS is needed, which should also include signs of neuroinflammation and deep sequencing for pathogen discovery."