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DESPITE many decades of sudden infant death syndrome research, mainstream researchers have not yet constructed a congruent and plausible patho-mechanism for these deaths.
Most research so far has been arbitrary in terms of epidemiology and pathology and has had little, if any, regard to the findings in physiologically monitored SIDS cases captured on memory monitors, or consistency of pathological findings.
However, an infection model of SIDS may provide some answers. Because of the importance of the gut microbiome in the development of the infant immune system and maintaining the physiological integrity of the gut, I was part of a team that conducted an investigation into the gut microbiome of SIDS and live babies.
Previous sterile site findings and earlier research showed that Staphylococcus aureus and Escherichia coli were more often found in babies who died from SIDS than in those who died from other causes. Based on this work, we developed a hypothesis, similar to one outlined earlier, proposing that a brief bacteraemia occurred prior to death.
The hypothesis included pathogen recognition defectiveness supported by the finding of immune response (IR) gene defects, eg, IL-10 low-producer polymorphism. Bacteraemic episodes are common in early life, so “normal” babies who lack genetic IR defects would be better able to cope with these events and survive the bacteraemia without an adverse outcome.
The bacteraemia could result from defective gut wall integrity or defences. An altered or “abnormal” gut microbiome may influence gut defences or cause possible inflammation and therefore could affect translocation of pathogens such as S. aureus and certain pathotypes of E. coli resident in the infant gut. Extraintestinal and uropathogenic E. coli pathotypes are overrepresented in SIDS cases as is S. aureus.
Our research showed significant changes in gut microflora occurred with age and these differed significantly between SIDS and “control” babies, suggesting that factors influencing colonisation of the gut in SIDS infants during the first few months of life differ from those of live comparison babies. This could imply that the gut itself, and/or the innate and/or adaptive immune systems of SIDS infants are compromised in some way. We suggest an “abnormal” gut microbiome could be responsible.
The research also showed the gut microbiome of SIDS babies differs from that of normal babies, particularly the overarching finding of significantly more babies dying while lying prone, with S. aureus colonisation, than babies similarly colonised but dying in other positions (supine/side). This supports the hypothesis that prone sleep position increases the risk of such colonisation and therefore provides a congruent explanation as to why sleeping prone increases SIDS risk. There was a highly significant association between prone sleeping and S. aureus in both gut and a sterile site.
Considered together with our findings, the theory that bacterial infection plays a role in the final events of SIDS is supported by a large body of evidence — sterile site swabs indicate bacteraemia and we know that bacteraemia is a profound inducer of hypoxaemia (seen in the terminal stages); there is evidence that fever precedes some SIDS deaths; and pathological findings of intrathoracic petechiae, heavy wet lungs and liquid blood/elevated fibrin degradation products that are all compatible with a process of bacterial sepsis, together with the physiological findings of hypoxaemia and bradycardia and asystole followed by gasping. These observations point to the possibility that bacterial sepsis/toxaemia is the final event in SIDS pathogenesis.
Therefore, arguments in favour of respiratory or brainstem compromise, one could contend, evaporate.
Our microbiome findings raise the possibility for trials of a prevention program to provide the “correct” microbiome to babies early in life. If sustained colonisation is achievable, this would be a simple and relatively cheap and novel approach to help eliminate this tragic and enigmatic condition.
Professor Paul Goldwater is a consultant in clinical microbiology and infectious diseases at SA Pathology (at the Women’s & Children’s Hospital, Adelaide).
Well, ten years have passed since this was published, so I’ll freshen things up. My hypothesis has it that diaphragm injury in bacterial and viral sepsis, along with numerous other diaphragm fatiguing factors (like fever/overheating, nicotine exposure, acidosis and prone positioning), increase the potential for neuromuscular excitation in the form of a diaphragm cramp (novel diaphragm cramp-contracture). This would paralyze the diaphragm causing silent respiratory arrest. Death would be rapid and unexpected, consistent with most SIDS deaths. To learn more, see my ResearchGate profile. Gebien.
Dear Dr Paul Goldwater: I had written you when I was in my BSN program, (2003), and the information with the curlin protein exotoxin as an antigen and a start to sepsis, severe sepsis, and septic shock was interesting in the etiology of SIDS, the most common cause of death in infants. You were kind enough to answer some of my emails. Thank you, and I hope a collaborative effort through the United States NIH, helps with effective SIDS prevention, either through passive blocking antibodies for immunity against the virulent O and H serotypes of E coli, and then later active immunity once the infant immune system is mature enough to make a good active response and establish active immunity against the SIDS antigens. (Analogous to the H BIG immunizations presently used). I am not in infectious diseases but I am an adult CCRN critical care nurse.
There is a fascinating case study in the AACN Advanced Critical Care journal, Vol. 30, No 2, pp 151 – 164, in the AACN literature banks, authored by Janice Skinner, CRNP-A. It describes a 39 yo male infected by a tick borne illness, erlichiosis, who has a hyperinflammation of the immune system, known as Hemophagocytic Lymphohistiocytosis, or HLH. She nicely describes the pathophysiologic mechanism, and also eludes to the highest incidence of HLH being in infants less than 3 months of age. It is most commonly an autosomal recessive primary familial pediatric disorder, with male to female incidence about equal, also with an ethnic predisposition, in East Asian persons with a malignancy. Later in the paper she describes a elevated ferritin and a elevated soluble interleukin 2 receptor assay, where these lab values have a high sensitivity and specificity for HLH, and a low Natural Killer Cell count. I did not know if your current research ever looked for a genetic predisposition for infants to get an “early” case of SIDS, age 0 to 3 months, or if anyone has looked into mutations in the HLH genes, which she says occurs in 14 to 25% of adults. I am new to immunology, but perhaps there is something to this and may have some relationship to an altered immune response in SIDS. In adult critical care, we have SIRS, SEPSIS, and a culture negative Severe Sepsis, Septic shock continuum, which might be somewhat analogous the immune “over inflammation,” which maybe undiagnosed HLH, that perhaps may also be involved in SIDS.
His treatment includes corticosteroids, decadron and or solumedrol, etopiside a DMARD, and stem cell transplant.
Thank you for all of the interesting research and I hope this note may add some additional useful information, with perhaps a new insight.
Hemophagocytic Lymphohistiocytosis
Janice Skinner et al
AACN Advanced Critical Care
Vol 30, No 2, pp. 151-164
2019@ AACN
Sorry to rain on the parade but the jury is still out on the issue of Sudden Infant Death and what causes it. Many many paediatric autopsies over decades have failed to show any convincing evidence of sepsis as a cause. I doubt very much sepsis from the gut is the explanation for many of these deaths, as appealing as the concept may be. The context of each death is very relevant and is easy to overlook in the search for “the cause” of the sudden death, assuming it “must” be due to a natural disease process. Don’t forget to look at the effects of co-sleeping/bedsharing/unsafe sleeping environments in many of these cases before jumping to conclusions about the so-called perils of bacteria in kids’ guts. We simply don’t know what happens to little kids when they are in bed with large (and getting larger) adults.
Thank you Dr. Goldman
I love how modern research is confirming so many time honoured Naturopathic and old school medical understanding. Hippocrates mentioned that all disease begins in the gut some 2000 yeas ago, conversely good health begins in the gut..
Dr Goldwater,
Thank you for identifying the importance of communication between specialist researchers, clinicians, and components of biological organisms.
I understand that some regard the brain and the cardiovascular systems as inextricably linked to the immune system, acquired and innate, in autoimmunity, nervous tissue pathophysiology, and to the gut and microbiome by extension. IL-10 and its receptors have important regulatory role in homeostasis generally. Glial cells, monocytes, and macrophages have commonalities and communicate across the blood-brain barrier. Irritable and Inflammatory Bowel Disease, asthma, allergy, vascular endothelial cardiac and coagulopathic dysfunction, epilepsy, Depression, Schizophrenia, Rheumatoid Arthritis are associated with disturbed IL-10 signalling. To separate the actions of, for example, the pre-Botzinger Nucleus on cardiac and respiratory functions from immune reactions to bacterial and viral load, or to say that the argued contribution of brainstem compromise to Sudden Unexpected Death in Infancy could evaporate, might be hot air.
Beth.
The author makes a link between sleeping position and microbiological colonisation. Could Prof Goldwater please explain how thse two factors might interact, and which might be chicken vs egg? HOw would sleeping position lead to differential organism colonisation?
As an experienced midwife and maternal & child health nurse I have long rationalised that there are reasons not yet found for SIDS. Thank you Paul Goldwater this is fascinating information. It would also be interesting to increase our knowledge with information about the type of birth and place of birth and colonisation at birth in relation to these bacteria. It is my understanding that Staph aureus is hospital acquired so are then any differences in colonisation of babies born in hospital, both abdominal and vaginal (instrumental and non-instrumental) and the vaginal birth of babies born at home.
Fascinating, thought provoking hypothesis. We are opening up a previously undiscovered universe.
Why do we not see evidence of this septisaemia at other times? ie while they are awake?