Enterovirus and Parechovirus Coinfection in a Sudden Unexpected Infant Death Enagnon Kazali Alidjinou, MD, PhD,a,b Marine Dorsi Di Meglio, MD,c Antoine Biron, PharmD,a Marion Jeannoel, PharmD,d Isabelle Schuffenecker, PharmD, PhD,d Ann-Claire Gourinat, PharmDa

Viruses are suspected to play a role in the multifactorial pathogenesis of abstract sudden infant death. We described a sudden and unexpected death in a 5- month-old boy, with detection of both enterovirus and parechovirus RNA in the blood. This is the first report of a dual viraemia of enterovirus and parechovirus and its potential association with a sudden unexpected infant aMicrobiology Laboratory, Centre Hospitalier Territorial de Nouvelle-Calédonie, Dumbea, New Caledonia; bLaboratoire death. Extensive sampling and testing especially using molecular methods de Virologie ULR 3610, Université Lille, Centre Hospitalier currently available is needed to better understanding the “hypothetical” link Universitaire de Lille, Lille, France; cService de Néonatologie, Centre Hospitalier Territorial de Nouvelle-Calédonie, between viral infections and sudden infant death. Dumbea, New Caledonia; and dLaboratoire de Virologie, Centre National de Référence Entérovirus et Parechovirus, Centre Hospitalier Universitaire de Lyon, Lyon, France

Dr Alidjinou conceptualized and designed the study, Sudden unexpected infant death (SUID) Historically, several factors have been drafted the initial manuscript, and reviewed and is defined by the Centers for Disease reported to contribute to a baby’s risk revised the manuscript; Drs Dorsi Di Meglio, Biron, Control and Prevention as a death of SIDS, including male sex, prone and Gourinat collected clinical and laboratory data , and critically reviewed the manuscript for important occurring among infants 1 year old sleeping, exposure to cigarette smoke, intellectual content; Drs Jeannoel and Schuffenecker 6 and with no immediately obvious young age, and nonwhite ethnicity. The performed virus sequencing analyses and reviewed cause.1 These deaths occur suddenly currently admitted pathogenesis of and revised the manuscript; and all authors and may be explained or unexplained SIDS suggests a “triple risk” hypothesis, approved the final manuscript as submitted and agree to be accountable for all aspects of the work. and commonly include 3 components: in which an infant with underlying sudden infant death syndrome (SIDS), vulnerability is subjected to an extrinsic Dr Alidjinou’s current affiliation is Laboratoire de Virologie, Centre de Biologie Pathologie, CHU de Lille, death from unknown cause, and death risk factor during a critical stage of his 2 Lille, France. from accidental suffocation and or her development. An underlying DOI: https://doi.org/10.1542/peds.2019-3686 strangulation in bed.2 SUID remains infection has been previously suggested one of the most common causes of to play a role in the pathogenesis of Accepted for publication Feb 10, 2020 fi postneonatal infant death in developed SIDS, on the basis of autopsy ndings Address correspondence to Dr Enagnon Kazali fl Alidjinou, MD, PhD, Centre Hospitalier Territorial de countries. In the United States, there (infection or in ammation markers) Nouvelle-Calédonie, Microbiology Laboratory, 98835 ∼ and results of studies in which were 3600 SUIDs reported in 2017, Dumbea, New Caledonia. including ∼1400 deaths from SIDS, researchers report detection of E-mail: [email protected] infectious agents.7,8 Viruses were 1300 deaths from unknown causes, PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, and 900 deaths from accidental especially suspected, because of 1098-4275). 1 epidemiological features of SIDS (peak suffocation and strangulation in bed. Copyright © 2020 by the American Academy of incidence in winter months), to directly SIDS strictly refers to a death in Pediatrics or indirectly play a role.7 a seemingly healthy infant ,1 year that FINANCIAL DISCLOSURE: The authors have indicated occurs during the sleep period or in the Enteroviruses and parechoviruses are they have no financial relationships relevant to this transition between sleep and waking, a frequent cause of infection in children article to disclose. and which cannot be explained after that are commonly associated with mild FUNDING: No external funding. a thorough case investigation including disease, although sometimes, especially autopsy.3,4 However, this diagnosis of in young children, they can lead to To cite: Alidjinou EK, Dorsi Di Meglio M, Biron A, exclusion also depends on the accuracy a more severe disease such as et al. Enterovirus and Parechovirus Coinfection and completeness of the meningitis, encephalitis, myocarditis, or in a Sudden Unexpected Infant Death. Pediatrics. 2020;146(3):e20193686 investigations.5 sepsis-like illness.9,10

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 3, September 2020:e20193686 CASE REPORT In this study, we report a coinfection indicative of a severe degree of and respiratory samples were with enterovirus and parechovirus in encephalopathy. Transcranial negative for these viruses. a context of sudden and unexpected ultrasound and cranial MRI also death in a 5-month-old boy. found a pattern of anoxic-ischemic The positive sample was sent to encephalopathy. French enteroviruses and parechoviruses reference laboratory CASE PRESENTATION for confirmation and virus typing. A 5-month-old male infant, who was LABORATORY INVESTIGATIONS Enterovirus isolate was found to be Enterovirus-C99, and the kept in a nursery, drank a bottle of The blood gas sample on admission milk early in the afternoon. He was parechovirus isolate was typed as showed a pH of 6.7, with PCO2 at 61 put to bed 3 hours later because he Parechovirus-1. mm Hg, PO2 at 54 mm Hg, seemed tired. A few minutes later, his bicarbonates at 7.8 mmol/L, base parents came to pick him up and excess at 228, and lactates at 17 TREATMENT AND OUTCOME found a pale and nonreactive boy. mmol/L. Blood chemistry (post-CPR) The resuscitation was continued in Cardiopulmonary resuscitation (CPR) was significant for elevated levels of the ICU with mechanical ventilation, was started until the arrival of the potassium (7.5 mmol/L, due to fluid therapy, and adrenaline Urgent Medical Aid Service difficult venipuncture), aspartate administration. Antimicrobial therapy ambulance. An endotracheal transaminase (583 IU/mL), alanine with cefotaxime, gentamycin, and intubation was performed with transaminase (393 IU/L), creatine clindamycin was initiated on subsequent mechanical ventilation, phosphokinase (2559 IU/mL), and admission. Death occurred 2 days and an intraosseous needle was troponin (254 pg/mL). The C-reactive postadmission, after episodes of heart placed. The administration of protein was normal. The blood cell rhythm disorders in a context of adrenaline allowed recovery of count found an increase in white fl multiple organ failure. An autopsy cardiac activity. The no- ow period blood cells (32 g/L), with was not performed, according to the was estimated to be 15 minutes. The a lymphocyte predominance (63%) parents’ will. morning at the nursery was as usual. and pleomorphic morphology on the A brief medical history found that the blood smear. Rapid toxic screening in pregnancy was normal, with a term urine was negative except for DISCUSSION delivery followed by normal neonatal acetaminophen, and the high- growth. The personal and familial performance liquid chromatography Sudden death is always dramatic for history was unremarkable. method allowed detection of both parents and caregivers. The case Nevertheless, he had nasal congestion acetaminophen, clindamycin, and described in this report occurred in for a few days, with recent probably a corticosteroid molecule. A New Caledonia, where the incidence ∼ improvement. lumbar puncture was performed, and of SUID seems to be high ( 8 cases per year in the pediatric units of the Thereafter, the boy was admitted to cerebrospinal fluid (CSF) testing territorial hospital, according to the NICU. On admission, the showed 1 white blood cell and 3 red 3 unpublished data). In this case, the temperature was at 33.5°C and the blood cells per mm , a protein level at stool sample was found positive for weight was at 6 kg. A few papules 0.58 g/L, and glucose at 1 mmol/L. adenovirus, enterovirus and were observed on the face. No Lactates were normal and CSF culture parechovirus, and more importantly, purpura or signs of injury were result was negative. Urine and blood enterovirus and parechovirus were found. The neurologic examination cultures also remained negative. detected in the blood. A link between was significant for an unconscious Virology investigations initially these findings and the sudden death infant (Glasgow coma scale at 3 include a respiratory sample tested might be possible. A heart disease, without sedation) with a global negative for influenza viruses and especially a myocarditis triggered by hypotonia and areflexia and bilateral respiratory syncytial virus, and CSF 1 or both viruses is a possible dilated nonreactive pupils. The sample was negative for herpes scenario for the infant death. cardiopulmonary examination was simplex virus and enterovirus. Then, Unfortunately, such conclusion initially normal, but the condition a stool sample was tested by using cannot be definitively made without rapidly worsened, with the alteration the FTD EPA one-tube multiplex autopsy and pathology data. There of respiratory and hemodynamic assay (Fast Track Diagnostics) and was no clinical or ultrasound parameters and the occurrence of was found positive for enterovirus, evidence for myocarditis on myocardial edema. parechovirus and adenovirus. admission, but a myocardial edema The electroencephalography was Enterovirus and parechovirus were was later observed, probably because “nearly flat,” with low voltage activity, also detected in a blood sample. CSF of CPR.

Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 ALIDJINOU et al Enterovirus-induced myocarditis has Parechovirus-3 infection has been excluded that the presence of one or been frequently suspected in SIDS previously described in infant sudden their combination could increase the with viral detection (mostly group B deaths.16,17 vulnerability to death in adjunction of coxsackieviruses) in tissue samples.11 additional stressors. Enterovirus strain was typed as There is some evidence suggesting Enterovirus-C99, which is a new type a role for infectious agents and recently described within especially viruses in SIDS, even if no CONCLUSION 7 Enterovirus-C species. Enterovirus- clear association has been found. In This is the first report of a dual C99 is close to coxsackievirus-A 24 fact, the pathogenesis of SIDS is viremia of enterovirus and type (82%–87% VP1 amino-acid multifactorial, and according to the “ ” parechovirus, and its potential identity), but there is a clear triple risk model, viral infections association with an SUID. phylogenetic and antigenic distinction could play a role as exogenous trigger between both types.12 Enterovirus- like other factors such as sleep Extensive sampling and testing, C99 has not been associated with patterns. Viruses can potentially especially by using molecular severe disease but has been contribute to all the possible methods currently available, is frequently detected in patients with mechanisms described for sudden needed to improve our understanding acute flaccid paralysis.13,14 death, including respiratory failure, of the “hypothetical” link between cardiovascular dysfunction, viral infections and sudden infant The Parechovirus-1 strain showed gastrointestinal dysfunction, and death and maybe to exclude the use 87% to 90% similarity with others nervous system abnormalities. In fi of a SIDS diagnosis in several cases. reported in the Asia-Paci c region addition, the immune response to after 2010. Among the 19 genotypes viral agents could be a key currently described, Parechovirus-1 is component contributing to death in ABBREVIATIONS the most prevalent genotype and immunologically incompetent infants CPR: cardiopulmonary mostly associated with mild or those with hypersensitive immune 18 resuscitation gastrointestinal or respiratory illness, responses. whereas Parechovirus-3 seems to be CSF: cerebrospinal fluid the most clinically important In our case, there is no conclusive SIDS: sudden infant death genotype because of its association evidence of the viral agents being syndrome with severe illness in younger infants, responsible for death, because the SUID: sudden unexpected infant including sepsis-like and central types identified are not the most death nervous system infections.15 virulent ones, but it cannot be

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 3, September 2020 3 syndrome: a prospective postmortem L20B-cell-culture-negative stool 17. Sedmak G, Nix WA, Jentzen J, et al. study. Pediatr Res. 2004;55(6):947–952 samples from children Infant deaths associated with fl 12. Brown BA, Maher K, Flemister MR, et al. diagnosed with acute accid paralysis human parechovirus infection in Resolving ambiguities in genetic typing in Nigeria. Arch Virol. 2017;162(10): Wisconsin. Clin Infect Dis. 2010;50(3): – of human enterovirus species C clinical 3089 3101 357–361 fi isolates and identi cation of 15. Olijve L, Jennings L, Walls T. Human 18. Duncan JR, Byard RW. Sudden infant enterovirus 96, 99 and 102. J Gen Virol. parechovirus: an increasingly death syndrome: an overview. In: 2009;90(pt 7):1713–1723 recognized cause of sepsis-like illness Duncan JR, Byard RW, eds. SIDS 13. Cabrerizo M, Rabella N, Torner N, et al. in young infants. Clin Microbiol Rev. Sudden Infant and Early Molecular identification of an 2017;31(1):e00047-17 Childhood Death: The Past, the Present enterovirus 99 strain in Spain. Arch 16. Schuffenecker I, Javouhey E, Gillet Y, and the Future. Adelaide, Australia: – Virol. 2012;157(3):551 554 et al. Human parechovirus infections, University of Adelaide Press; 2018. 14. Adeniji JA, Oragwa AO, George UE, Ibok Lyon, France, 2008-10: evidence for Available at: www.ncbi.nlm.nih.gov/ UI, Faleye TOC, Adewumi MO. severe cases. J Clin Virol. 2012;54(4): books/NBK513399/. Accessed August Preponderance of enterovirus C in RD- 337–341 23, 2019

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 Enterovirus and Parechovirus Coinfection in a Sudden Unexpected Infant Death Enagnon Kazali Alidjinou, Marine Dorsi Di Meglio, Antoine Biron, Marion Jeannoel, Isabelle Schuffenecker and Ann-Claire Gourinat Pediatrics 2020;146; DOI: 10.1542/peds.2019-3686 originally published online August 18, 2020;

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