Investigating meningitis in cases of sudden and unexpected death in infancy (SUDI) at the Tygerberg Medico-legal Mortuary in the Western Cape Metropole

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dc.contributor.advisorDe Beer, Corenaen_ZA
dc.contributor.advisorVerster, Janetteen_ZA
dc.contributor.advisorNel, Pieteren_ZA
dc.contributor.authorNortjé, Simoné-Odetteen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Medical Virology.en_ZA
dc.date.accessioned2023-02-22T03:18:51Zen_ZA
dc.date.accessioned2023-11-16T08:08:53Zen_ZA
dc.date.available2023-02-22T03:18:51Zen_ZA
dc.date.available2023-11-16T08:08:53Zen_ZA
dc.date.issued2023-02en_ZA
dc.descriptionThesis (MMed)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH ABSTRACT: The infant mortality rate in South Africa is currently 24.3 per 1 000 live births, with infections accounting for the majority of infant deaths. All unexplained deaths between the ages of seven days and one year that occur before any investigation has taken place are classified as Sudden Unexpected Death in Infancy (SUDI). Sudden Infant Death Syndrome (SIDS) is the classification assigned to cases where no cause of death could be found, after conclusion of the investigation. An interlinking of several factors is widely accepted to contribute to the occurrence of unexplained infant death, but one possible cause, infective meningitis, has largely remained unexplored and underreported despite the regular detection of viral and bacterial pathogens in SUDI post-mortem specimens. The investigators postulate that these pathogens could contribute as an exogenous trigger to SUDI in a susceptible infant during a particular developmental phase and set out to investigate the exact contribution of meningeal pathogens in SUDI cases. The primary aim of this study was to investigate the presence of viral and bacterial pathogens, commonly associated with meningitis, isolated from cerebrospinal fluid (CSF) as either single or co-infections, over the course of one year from all SUDI cases admitted to Tygerberg Medico-legal Mortuary. The secondary aim was to investigate the prevalence of neonatal meningitis in the Eastern Metropole of Cape Town in the Western Cape by performing a retrospective review on all infants under the age of one year admitted to Tygerberg Hospital that were diagnosed with suspected meningitis due to viral, bacterial and tuberculosis causes over a five-year period (2016 to 2021). Additionally, an ancillary investigation was conducted to determine if the modified CSF extraction technique has a lower risk of contamination. Methods Post-mortem samples were collected from 133 SUDI cases that were admitted to the Tygerberg Medico-Legal Mortuary between March 2021 and March 2022. CSF collected during the autopsies was investigated for the presence of certain viruses and bacteria that are commonly associated with meningitis. Two multiplex assays specific for the various pathogens in question were used to analyse extracted deoxyribonucleic acid (DNA). The one-step multiplex real-time polymerase chain reaction (PCR) assay, Seegene AllplexTM Meningitis-V1 Assay was used for the detection of seven double-stranded DNA human herpes viruses (HHV-1 to HHV-7). The one-step multiplex real-time PCR assay, Seegene AllplexTM Meningitis-B Assay was used for the detection of six bacterial pathogens including Group B Streptococcus, Escherichia coli, Haemophilus influenzae type b, Listeria monocytogenes, Neisseria meningitidis and Streptococcus pneumoniae. Fresh CSF samples were analysed with the Xpert® MTB/RIF Ultra assay in order to detect Mycobacterium tuberculosis. Data were stored securely in an encrypted Microsoft® Office® Excel® database. Results Multiple well-known demographic risk factors for SUDI were observed, such as age 11.3 ± 9.9 weeks, majority males, cold season, prematurity, low birthweight, bed-sharing, prone sleeping position, little to no ventilation, exposure to smoke and young maternal age. With the AllplexTM Meningitis-V1 and Meningitis-B real-time PCR, 24% (31/131) of cases had viral pathogens detected and 9% (12/131) had bacterial pathogens detected. HHV-6 (47%) and cytomegalovirus (23%) were the most commonly detected viruses. A significant association was observed between viral PCR-positive results and age, with a peak incidence between 10 and 14 weeks. Neisseria meningitidis (42%) and Haemophilus influenzae type b (25%) were the most frequently detected bacteria. Most PCR-positive cases were identified during the cold season. With the Xpert® MTB/RIF Ultra assay, no tuberculosis meningitis was detected over a six-month period. Infection was the most frequent cause of death (COD) in cases, with a significance observed between both PCR-positive viral (p=0.017) and bacterial (p=0.002) results and a COD of Infection. Five percent (7/131) of the cases were signed out as meningitis as final diagnosis, of which Neisseria meningitidis was detected in two of those cases. The retrospective audit showed PCR-positive results for any of the six HHVs in 21% (213/1 037) of cases. HHV-6 was positive most often in 43% (91/213) of samples, followed by CMV in 27% (58/213), EBV in 17% (37/213), VZV in 5% (11/213), HHV-2 in 4% (8/213) and HHV-1 in 4% (8/213). No HHV-7 was detected over the five-year period. In total 6 535 CSF samples were cultured and of those 1% (65/6 535) were positive for one or more bacteria. Thirty-five percent (23/65) were positive for natural skin flora, 20% (13/65) each for E. coli and K. pneumoniae, 15% (10/65) for Staphylococcus aureus and 9% (6/65) for mixed growth. Conclusion In some cases that were assigned a COD of SIDS, the PCR results cannot be ignored. If performed routinely, the PCR results could have favoured a final COD of Infection instead of SIDS in some of these cases. Further research is needed to elucidate the significance of detecting pathogens from SUDI cases where no other ancillary investigations yield evidence of infection. Although only five cases of Neisseria meningitidis were detected, the severity of the pathogen cannot be ignored since two of those cases were assigned a final COD of meningitis. This finding supports the need for further investigations on the prevalence of Neisseria meningitidis in South Africa and whether or not meningococcal vaccines need to be reinstated in the Expanded Immunisation Program of South Africa.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Agtergrond Die babasterftesyfer in Suid-Afrika is tans 24.3 per 1 000 lewende geboortes, met infeksies wat verantwoordelik is vir die meerderheid van babasterftes. Alle onverklaarbare sterftes in babas tussen die ouderdom van sewe dae en een jaar wat plaasvind voordat enige ondersoek plaasgevind het, word geklassifiseer as Skielike onverwagse sterftes in babas (SUDI). Skielike babadoodsindroom (SIDS) is die klassifikasie wat toegeken word aan gevalle waar geen oorsaak van dood gevind kon word na afloop van die ondersoek nie. Interaksie tussen verskeie faktore dra waarskynlik by tot die voorkoms van SIDS, maar ten spyte daarvan dat verskeie virusse en bakterieë gereeld in SUDI nadoodse monsters bevestig word, is infektiewe breinvliesontsteking as ‘n oorsaak van dood in SUDI gevalle, nog nie voorheen ondersoek en gerapporteer nie. Die navorsers spekuleer dus dat hierdie organismes bydra tot SUDI in die vorm van 'n eksogene sneller in ‘n kwesbare baba tydens 'n spesifieke ontwikkelingsfase. Die presiese bydrae van meningitis-verwante patogene in SUDI-gevalle moet dus ondersoek word. Hierdie studie het primêr ten doel gehad om die teenwoordigheid van virusse en bakterieë wat algemeen met breinvliesontsteking geassosieer word, in SUDI gevalle te ondersoek. Serebrospinale vog (SSV) is oor ‘n tydperk van een jaar by al die SUDI gevalle wat by die Tygerberg Medies-geregtelike Lykshuis opgeneem is, versamel en enkel- of ko-infeksies van die organismses is ondersoek. Die sekondêre doel was om die voorkoms van neonatale breinvliesontsteking in die Kaapstad Oostelike-Metropool in die Wes-Kaap te ondersoek deur 'n retrospektiewe oorsig uit te voer op alle babas onder die ouderdom van een jaar wat in die Tygerberg-hospitaal opgeneem is en wat met virale, bakteriële en tuberkulose breinvleisonstekking gediagnoseer is oor 'n tydperk van vyf jaar (2016 tot 2021). Metodes Nadoodse monsters is versamel van 134 SUDI gevalle wat tussen Maart 2021 en Maart 2022 in die Tygerberg Medies-geregtelike Lykshuis opgeneem is. SSV wat tydens die lykskouings versamel is, was ondersoek vir die teenwoordigheid van sekere virusse en bakterieë wat algemeen met breinvliesontsteking geassosieer word. Twee multiplekstoetse spesifiek vir die verskillende patogene ter sprake is gebruik om geïsoleerde deoksiribonukleïensuur (DNS) te ontleed. Die een-stap multipleks intydse polymerase kettingreaksie (PKR)-toets, Seegene AllplexTM Meningitis-V1 Assay is gebruik vir die opsporing van sewe dubbelstring DNS menslike herpesvirusse (HHV-1 tot HHV-7). Die een-stap multipleks intydse PKR-toets, Seegene AllplexTM Meningitis-B-toets is gebruik vir die opsporing van ses bakteriële patogene, insluitend Groep B Streptococcus, Escherichia coli, Haemophilus influenzae tipe b, Listeria monocytogenes, Neisseria meningitidis en Streptococcus pneumoniae. Vars SSV monsters is met die Xpert® MTB/RIF Ultra-toets ontleed om Mycobacterium tuberculosis op te spoor. Data is gekodeer en veilig gestoor in 'n Microsoft® Office® Excel® databasis. Resultate Verskeie bekende demografiese risikofaktore vir SUDI is ook in hierdie studie gevind, soos die 11.3 ± 9.9 weke ouderdom, meerderheid manlike babas, koue seisoen, premature geboortes, lae geboortegewig, bed-deling, maag slaapposisie, min tot geen ventilasie, blootstelling aan sigaret rook en jong moeders. Met die “AllplexTM Meningitis-V1 en Meningitis-B Assay” PKR, is virale patogene in 24% (31/131) van gevalle bevestig en bakteriële patogene in 9% (12/131). HHV-6 (47%) en sitomegalovirus (23%) het die meeste voorgekom. ‘n Statisties-beduidende assosiasie is waargeneem tussen virale PKR-positiewe resultate en ouderdom, met die hoogste voorkoms in die 10 tot 14 weke ouderdomsgroep. Neisseria meningitidis (42%) en Haemophilus influenzae tipe b (25%) was die bakterieë wat die meeste voorgekom het. Die meeste PKR-positiewe gevalle is tydens die koue seisoen geïdentifiseer. Die “Xpert® MTB/RIF Ultra Assay” kon geen tuberkulose-breinvliesontsteking oor 'n tydperk van ses maande identifiseer nie. Infeksie was die mees algemene oorsaak van dood, met 'n beduidendheid waargeneem tussen beide PKR-positiewe virale (p=0.017) en bakteriese (p=0.002) resultate en 'n oorsaak van dood van Infeksie. Vyf persent (7/131) van die gevalle is finaal as breinvliesontsteking gediagnoseer, waarvan Neisseria meningitidis in twee van daardie gevalle teenwoordig was. Gevolgetrekking In sommige gevalle waar SIDS as die oorsaak van dood aangeteken is, kan die PKR-resultate nie geïgnoreer word nie. Indien PKR op ‘n roetine basis uitgevoer kon word, kon die PKRresultate in sommige van hierdie gevalle 'n finale oorsaak van dood as gevolg van infeksie in plaas van SIDS ondersteun het. Verdere navorsing is nodig om die belangrikheid van die opsporing van patogene in SUDI-gevalle uit te lig waar bykomende ondersoeke geen ander bewyse van infeksie oplewer nie. Alhoewel slegs vyf gevalle van Neisseria meningitidis opgespoor is, kan die belangrikheid van die patogeen nie geïgnoreer word nie, aangesien die diagnose en oorsaak van dood in twee van daardie gevalle breinvliesontsteking was. Hierdie bevinding onderstreep die belangrikheid om weer meningokokke-entstowwe in die Uitgebreide Immuniseringsprogram van Suid-Afrika in te sluit.af_ZA
dc.description.versionMastersen_ZA
dc.format.extentxviii, 109 pagesen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/128683en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshMeningitis in children -- Cape Town (South Africa)en_ZA
dc.subject.lcshInfants -- Mortality -- Cape Town (South Africa)en_ZA
dc.subject.lcshSudden infant death syndrome -- Cape Town (South Africa)en_ZA
dc.subject.lcshSudden unexpected death in infancy -- Cape Town (South Africa)en_ZA
dc.subject.lcshCerebrospinal fluid -- Cape Town (South Africa)en_ZA
dc.subject.lcshPathogenic microorganisms -- Cape Town (South Africa)en_ZA
dc.subject.lcshNeonatal infections -- Cape Town (South Africa)en_ZA
dc.titleInvestigating meningitis in cases of sudden and unexpected death in infancy (SUDI) at the Tygerberg Medico-legal Mortuary in the Western Cape Metropoleen_ZA
dc.typeThesisen_ZA
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