Correspondence
Sudden Infant Death Syndrome
N Engl J Med 2009; 361:2580-2582December 24, 2009
- Article
To the Editor:
Kinney and Thach (Aug. 20 issue)1 review the putative terminal respiratory pathway associated with the sudden infant death syndrome (SIDS), and they indicate a life-threatening event and failure of arousal as the first steps in the respiratory pathway to SIDS. The authors mention only central cortical and subcortical structures involved in arousal mechanisms, without referring to peripheral arterial chemoreceptors as the carotid body, the role of which in arousal from asphyxial events is widely accepted. Prematurity and exposure to smoke also increase the risk of SIDS and adversely affect the response of the peripheral arterial chemoreceptors.2,3 These chemoreceptors undergo structural and functional development during the postnatal period, with a gradual increase in hypoxic sensitivity.3,4 Prematurity causes intrinsic abnormalities of the response of the peripheral arterial chemoreceptors, which may be further worsened by prematurity-associated intermittent hypoxic events or oxygen therapy. Intermittent hypoxia may cause hypersensitivity of the peripheral arterial chemoreceptors, which may increase the risk of SIDS, precipitating unstable respiration through apneic responses after sighs or brief arousals.2-4 Conversely, exposure to hyperoxia has been reported to cause hyposensitivity of the peripheral arterial chemoreceptors, possibly leading to an ineffective response. Perinatal exposure to nicotine also blunts the function of the peripheral arterial chemoreceptors through changes in expression of neurotransmitters and neuromodulators.3-5
Andrea Porzionato, M.D., Ph.D.
Veronica Macchi, M.D., Ph.D.
Raffaele De Caro, M.D.
University of Padua, Padua, Italy
raffaele.decaro@unipd. it No potential conflict of interest relevant to this letter was reported.
5 References1
Kinney HC ,Thach BT . The sudden infant death syndrome. N Engl J Med 2009;361:795-805
Full Text | Web of Science | Medline2
Gauda EB ,Cristofalo E ,Nunez J . Peripheral arterial chemoreceptors and sudden infant death syndrome. Respir Physiol Neurobiol 2007;157:162-170
CrossRef | Web of Science | Medline3
Porzionato A ,Macchi V ,Parenti A ,Matturri L ,De Caro R . Peripheral chemoreceptors: postnatal development and cytochemical findings in Sudden Infant Death Syndrome. Histol Histopathol 2008;23:351-365
Web of Science | Medline4
Gauda EB ,Carroll JL ,Donnelly DF . Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors: invited article. Adv Exp Med Biol 2009;648:243-255
CrossRef | Web of Science | Medline5
Holgert H ,Hokfelt T ,Hertzberg T ,Lagercrantz H . Functional and developmental studies of the peripheral arterial chemoreceptors in rat: effects of nicotine and possible relation to sudden infant death syndrome. Proc Natl Acad Sci U S A 1995;92:7575-7579
CrossRef | Web of Science | Medline
To the Editor:
In discussing the causes of SIDS, Kinney and Thach focus on aberrant arousal mechanisms in the brain, particularly in the medulla.
We have shown that the Ljungan virus is present in infants with SIDS.1 This evidence extends beyond the small fraction of cases of SIDS that are associated with rare infectious agents and observations that incidental infections from well-known agents may also be present. In our work, the incidence of the syndrome in humans was correlated with the cyclic numbers of native rodent carriers of Ljungan virus in northern Sweden and the presence of the virus in several patients with SIDS and SIDS-related syndromes.1 We also reported on a patient with Ljungan virus in the medulla oblongata itself.1 Supporting data show that Ljungan virus is a factor in intrauterine fetal death2 and in central nervous system malformations in humans3; furthermore, this suite of perinatal outcomes was mimicked in a mouse model of Ljungan virus disease.4 The data point to a new hypothesis of SIDS causation due to a novel infectious agent.
William Klitz, Ph.D.
University of California, Berkeley, CA
klitz@berkeley.edu Bo Niklasson, M.D.
Apodemus, Stockholm, SwedenDr. Niklasson reports being a codirector of Apodemus and having several patents involving Ljungan virus. No other potential conflict of interest relevant to this letter was reported.
4 References1
Niklasson B, Almqvist PR. Hörnfeldt B, Klitz W. Sudden infant death syndrome and Ljungan virus. Forensic Sci Med Pathol 2009 May 1 (Epub ahead of print).
2
Niklasson B ,Samsioe A ,Papadogiannakis N , et al. Association of zoonotic Ljungan virus with intrauterine fetal deaths. Birth Defects Res A Clin Mol Teratol 2007;79:488-493
CrossRef | Web of Science | Medline3
Niklasson B ,Samsioe A ,Papadogiannakis N ,Klitz W . Zoonotic Ljungan virus associated with central nervous system malformations in terminated pregnancy. Birth Defects Res A Clin Mol Teratol 2009;85:542-545
CrossRef | Web of Science | Medline4
Samsioe A ,Feinstein R ,Saade G , et al. Intrauterine death, fetal malformation, and delayed pregnancy in Ljungan virus-infected mice. Birth Defects Res B Dev Reprod Toxicol 2006;77:251-256
CrossRef | Web of Science | Medline
To the Editor:
We have noted that in the United States, the excess risk of SIDS among boys is 50% (ratio of boys to girls, 3:2), not 100% (ratio of boys to girls, 2:1).1,2 Furthermore, an excess risk of SIDS among boys is not itself remarkable, because the rates of total deaths among infant boys in all disease categories except neoplasms, as listed in the International Classification of Diseases in the United States in the 1979–2005 period, were greater than the corresponding rates of deaths among infant girls.1,3 Rather, the consistent year-to-year 50% excess risk of SIDS among boys in the United States is remarkable because it implies a possible genetic recessive X-linked condition associated with a greater risk of SIDS among subsequent siblings of infants with SIDS.2,3
Kinney and Thach suggest that such previous cases of SIDS involving the same caretaker (or recurrent life-threatening events in an infant with SIDS) may indicate the possibility of infanticide. Fortunately, this concept changed in the United Kingdom in 2003 after three high-profile criminal prosecutions occurred.4 At trial, an expert witness famously said the chances of two siblings dying of SIDS were “73 million to one.”5 This statement helped to convict all three mothers who were later cleared after this notorious statistic was cast into disrepute.
David T. Mage, Ph.D.
Alfred I. duPont Hospital for Children, Wilmington, DE
magedonner@aol.com Marta Cohen, M.D.
Sheffield Children's Hospital, Sheffield, United KingdomMaria Donner, Ph.D.
DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DENo potential conflict of interest relevant to this letter was reported.
5 References1
Centers for Disease Control and Prevention, National Center for Health Statistics. Compressed mortality files 1979-2005. CDC WONDER On-line Database. (Accessed December 3, 2009, at http://wonder.cdc.gov/.)
2
Mage DT ,Donner EM . The fifty percent male excess of infant respiratory mortality. Acta Paediatr 2004;93:1210-1215
CrossRef | Web of Science | Medline3
Mage DT, Donner M. A unifying theory for SIDS. Int J Pediatrics 2009. (Accessed December 3, 2009, at http://downloads.hindawi.com/journals/ijped/2009/368270.pdf.)
4
Sudden unexpected death in infancy. London: The Royal College of Pathologists and The Royal College of Paediatrics and Child Health. (Accessed December 3, 2009, at http://www.rcpath.org/resources/pdf/SUDI%20report%20for%20web.pdf.)
5
Support, not suspicion, should be the first reaction to the tragedy of a cot death. The Independent. September 7, 2004. (Accessed December 3, 2009, at http://www.independent.co.uk/opinion/leading-articles/support-not-suspicion-should-be-the-first-reaction–to-the-tragedy–of-a-cot-death-550425.html.)
Author/Editor Response
We agree with Porzionato et al. that peripheral, as well as central, deficits in systems mediating hypoxic responses are important to consider in SIDS, and that analysis of the carotid body in SIDS merits attention. Different types of analyses have been reported to date in the carotid body in cases of SIDS, with conflicting results.1,2
We are aware of the study by Niklasson et al. concerning the potential role of the Ljungan virus in SIDS.3 We, however, do not find the evidence sufficiently compelling at present. The immunocytochemical study of virus expression in SIDS tissue sections was limited by a small sample size and a lack of controls (i.e., infants who died from known noninfectious causes). The photograph of viral expression in the article by Niklasson et al. shows, in our opinion, immunostaining in axonal fibers and not, as suggested, in neuronal-cell bodies, raising the possibility that this staining was nonspecific. A tissue control without the primary antibody was not shown for the reader's assessment of staining specificity.
Published studies of rates of SIDS and sex preponderance report different values, such that infant boys are 30 to 50% more likely than girls to be affected.4 In a study of the epidemiology of SIDS in Finland, the male-to-female ratio varied from 0.7 to 4.5, with a mean of 1.8.5 Thus, the sex ratio in SIDS varies according to different studies, including 2:1, as we cited in our article, and is not invariably 1:1.5, as cited by Mage et al. Their hypothesis of a possible genetic recessive X-linked condition associated with a greater risk of SIDS among subsequent siblings awaits confirmation. In this regard, one of us recently reported on a genetic mouse model of SIDS with male bias and a chromosome locus that was sex-specific.6 Finally, we thank Mage et al. for their thoughts about multiple deaths from SIDS in a family and the uncertain relationship of these deaths to infanticide. Infanticide, in our opinion, still remains in the differential diagnosis of more than one death from SIDS in a family.
Hannah Kinney, M.D.
Children's Hospital Boston, Boston, MA
hannah.kinney@childrens. harvard. edu Bradley T. Thach, M.D.
Washington University School of Medicine, St. Louis, MOSince publication of their article, the authors report no further potential conflict of interest.
6 References1
Lack EE ,Perez-Atayde AR ,Young JB . Carotid bodies in sudden infant death syndrome: a combined light microscopic, ultrastructural, and biochemical study. Pediatr Pathol 1986;6:335-350
CrossRef | Medline2
Paval Z ,Toro K ,Keller E ,Jung J . Morphometric investigation of carotid body in sudden infant death syndrome. Rom J Morphol Embryol 2005;46:93-97
Medline3
Niklasson B, Almqvist PR, Hörnfeldt B, Klitz W. Sudden infant death syndrome and Ljungan virus. Forensic Sci Med Pathol 2009 May 1 (Epub ahead of print).
4
Hunt CE ,Hauck FR . Sudden infant death syndrome. CMAJ 2006;174:1861-1869
CrossRef | Web of Science | Medline5
Rintahaka PJ ,Hirvonen J . The epidemiology of sudden infant death syndrome in Finland in 1969-1980. Forensic Sci Int 1986;30:219-233
CrossRef | Web of Science | Medline6
Thach BT ,Kenney-Hunt JP ,Simon TC , et al. Sex-specific quantitative trait loci linked to autoresuscitation failure in SWR/J mice. Heredity 2009;103:469-475
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Andrea Porzionato, Marcin Rucinski, Veronica Macchi, Carla Stecco, Ignazio Castagliuolo, Ludwik K. Malendowicz, Raffaele De Caro. (2011) Expression of leptin and leptin receptor isoforms in the rat and human carotid body. Brain Research 1385, 56-67
CrossRef
