A prospective study investigating the role of respiratory viral infections in Sudden Unexpected Death in Infancy (SUDI) at Tygerberg Medico-legal Mortuary

Ferreira, Janca (2020-03)

Thesis (MSc)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT: Background: The current South African infant mortality rate is 22.1 per 1 000 live births with respiratory infections, pneumonia, influenza and interstitial lung infections being responsible for most infant deaths. Sudden Unexpected Death in Infancy (SUDI) includes all infant deaths between the age of 7 days and 1 year without an apparent cause before any investigation has occurred. However, cases that remain unexplained following thorough investigation are classified as Sudden Infant Death Syndrome (SIDS). SIDS is regarded as a disease in search of a cause with several interlinking risk factors. Numerous respiratory viruses have been detected from SUDI autopsy specimens, therefore, viral infections could contribute to some SUDI cases as an exogenous trigger on a vulnerable infant during a specific developmental stage. This might be due to the infants’ vulnerability to infections due to immaturities of their immune systems. Nonetheless, the exact contribution of respiratory viruses preceding death still needs further investigation. Objectives: The primary aim of this study was to investigate the role of major respiratory viruses, found in the lungs and trachea as either single or co-infections of all SUDI cases admitted to Tygerberg Medico-legal Mortuary (MLM) over a 1-year period. The secondary aim entailed collecting all the epidemiological information and other relevant laboratory data from the retrospective cases from the Tygerberg MLM (2015-2016) to assess any trends or differences between the 2 studies and to evaluate how risk factors associated with SUDI cases at the Tygerberg MLM might have differed or remained constant over 2 study periods. Finally, laboratory results from all infants aged between 7 days and 1 year admitted to Tygerberg Hospital (TBH) due to respiratory infections during the study period were retrieved in order to identify if similar single and multiple viruses were circulating in both populations. Methods: Between March 2018 and March 2019 samples were collected from 173 SUDI cases admitted to Tygerberg MLM. As part of the mandatory routine investigations into SUDI cases bacterial culture swabs were collected from the lower left and right lung lobes at autopsy to investigate the role of single and co-infections of viruses associated with SUDI. The Seegene AllplexTM RV Essential Assay one-step multiplex, real-time Polymerase Chain reaction (PCR) assay was used for the detection of 6 ribonucleic acid (RNA) respiratory viruses, Influenza A (Flu A), Influenza B (Flu B), Human Metapneumovirus (HMPV), Human Parainfluenza virus (HPIV), Respiratory syncytial virus A and B (RSVA/B) and Human Rhinovirus (HRV) from RNA extracted from lower left and right lung lobe and tracheal swabs. Tissue sections from the lower left and right lung lobes were also assessed for histology signs of infection. TIBCO Statistica® version 13.5.0 was used to identify any similarities or differences between the current prospective study and retrospective study, as well as the comparison group of infants admitted to TBH. Results: During this study multiple known demographic risk factors for SUDI, such as age (12.1 ± 9.8 weeks), male predominance, prematurity, low birthweight, cold season, bedsharing, prone sleeping position and ventilation were observed. With the AllplexTM RV Essential real-time PCR assay between 1 and 5 viruses were detected in 90.2% (156/173) of cases. RSV A/B (31.7%) and HRV (24.8%) were the most commonly detected viruses. The majority of PCR-positive cases were detected in the cold season, with a statistical significance observed for Flu A (p = 0.04), Flu B (p = 0.04), HPIV (p = 0.03) and RSV (p = 0.02) and cold season. The most frequently detected co-infection was between RSVA/B and HRV. Thirty-three cases had 2 viruses detected, 5 had 3 viruses and 1 case had 5 different viruses (Flu A - Flu B - HMPV - RSV A/B - HRV). The majority of cases had a cause of death (COD) of Infection. Furthermore, Flu A was significantly associated with the COD Infection and Flu B with SIDS. In 4 SIDS cases with positive histology, positive viral PCR results were observed leading to a change in COD to Infection. Major differences between the prospective and retrospective studies included female predominance, COD of SIDS, HRV being the most frequently detected virus and co-infection only being observed in 3 cases (Flu A - HRV, Flu B - HRV; HPIV - HRV - RSV A/B). The same viruses were circulating in SUDI cases and the comparison group. Conclusion: In cases that had a COD of SIDS, the PCR viruses detected cannot be ignored, especially when it is supported by histological signs of infection as seen during this study Therefore, the use of real-time PCR could alter a COD Classification from SIDS to Infection. However, the role of single or co-infection with respiratory viruses in SUDI cases wherein no histological sign of infection was observed requires further investigation. Future research is needed to determine the exact role of co-infections in those who succumb to SUDI, more specifically how viral interactions play a role in disease progression and severity in a vulnerable infant. Finally, research should be aimed at determining the effect of PCR-positive viral results in the absence of histology to identify the true cause of vulnerability in infants.

AFRIKAANSE OPSOMMING: Agtergrond: Die huidige baba sterftesyfer in Suid-Afrika is 22.1 per 1 000 lewendige geboortes. Die meeste sterftes kan toegeskryf word aan respiratoriese infeksies, longontsteking, griep en interstisiële longinfeksies. Die skielike onverwagte dood van ‘n baba, of beter bekend as wiegiedood (SUDI), sluit alle onverwagte sterftes van babas tussen die ouderdom van 7 dae en 1 jaar in, voor enige ondersoek plaasgevind het. Gevalle wat na 'n deeglike ondersoek steeds onverklaarbaar bly, word geklassifiseer as “Sudden Infant Death Syndrome” (SIDS). Verskeie risikofaktore kan bydra tot wiegiedood, byvoorbeeld virale respiratoriese infeksies. Die toename kan toegeskryf word aan babas se kwesbaarheid vir infeksies as gevolg van hul onderontwikkelde immuunstelsel, maar die presiese bydrae van respiratoriese virusse in wiegiedood moet egter nog verder ondersoek word. Doelstellings: Die primêre doel van hierdie studie was om die rol van respiratoriese viruses wat alleen of in kombinasies in die longe en lugweë aangetref word, te ondersoek. Alle SUDI-gevalle wat gedurende 'n periode van 1 jaar by Tygerberg Geregtelik-geneeskundige Lykshuis (GGL) opgeneem is, was ondersoek. Die sekondêre doelwit was om alle epidemiologiese en laboratorium resultate van ‘n vorige studie wat tussen 2015 en 2016 by Tygerberg GGL plaasgevind het, te vergelyk met die huidige studie in 'n poging om ooreenkomste of verskille tussen die 2 studies te identifiseer en te ondersoek hoe risikofaktore geassosieer met SUDI gevalle by die Tygerberg GGL oor die 2 studieperiodes verskil of konstant gebly het. Laastens is laboratorium resultate van alle babas tussen 7 dae en 1 jaar wat tydens die studieperiode in Tygerberg-hospitaal (TBH) opgeneem is as gevolg van respiratoriese infeksies, verkry om te bepaal of dieselfde virusse in beide populasies voorgekom het. Metodes: Tussen Maart 2018 en Maart 2019 is monsters versamel van 173 SUDI-gevalle wat by Tygerberg GGL opgeneem is. As deel van die verpligte roetine-ondersoeke na SUDI-gevalle is bakteriële kultuurdeppers tydens die lykskouing van die linker- en regterlonge versamel. Om die rol van enkel- en mede virusinfeksies wat met SUDI verband hou, te ondersoek, is die “Seegene AllplexTM RV Essential Assay, one-step, multiplex, real-time PCR” toets gebruik vir die opsporing van 6 ribonukleïensuur (RNS) respiratoriese virusse. Die virusse sluit in Influenza A (Flu A), Influenza B (Flu B), Human Metapneumovirus (HMPV), Human Parainfluenza virus (HPIV), Respiratory syncytial virus A/B (RSVA/B) en Human Rhinovirus (HRV) vanaf RNS wat uit die longe en lugweë versamel is. Weefsel van die onderste linker- en regterlong lobbe is geëvalueer vir histologiese tekens van infeksie. TIBCO Statistica® weergawe 13.5.0 is gebruik om enige ooreenkomste of verskille tussen die huidige prospektiewe studie en retrospektiewe studie te identifiseer, sowel as die vergelykingsgroep wat in TBH opgeneem is. Resultate: Tydens hierdie studie is verskeie bekende demografiese risikofaktore vir SUDI waargeneem, soos ouderdom (12.1 ± 9.8 weke), meerderheid manlike geslag, prematuriteit, lae geboortegewig, koue seisoen, bed-deling, slaapposisie op die maag en ventilasie. Die PKR (polymerase kettingreaksie) toets het tussen 1 en 5 virusse in 90.2% (156/173) van die gevalle opgespoor; RSV A/B (31.7%) en HRV (24.8%) het die meeste voorgekom. Die meerderheid PKR-positiewe gevalle is in die koue seisoen opgespoor, met statisties-beduidende assosiasies vir Flu A (p = 0.04), Flu B (p = 0.04), HPIV (p = 0.03) en RSV (p = 0.02) en koue seisoen. RSV A/B en HRV is die kombinasie wat die meeste voorkom het. In 33 gevalle is 2 virusse opgespoor, 5 gevalle het 3 virusse gehad en 1 geval het 5 verskillende virusse gehad (Flu A - Flu B - HMPV - RSV A/B en HRV). Die oorsaak van dood (OVD) in die meeste gevalle was Infeksie, Flu A was statisties-beduidend geassosieer met die OVD-infeksie en Flu B met SIDS. In 4 SIDS-gevalle met positiewe histologie, is mede-infeksie ook waargeneem. Die teenwoordigheid van hierdie mede-infeksies het gelei dat die OVD verander is na Infeksie. Aspekte waar die retrospektiewe studie van die prospektiewe studie verskil het, was die meerderheid vroulike geslag, meer gevalle het ‘n OVD van SIDS gehad, HRV was die virus wat die meeste opgespoor is en mede-infeksie is slegs in 3 gevalle waargeneem (Flu A - HRV, Flu B - HRV; HPIV - HRV - RSV A/B). Dieselfde virusse het voorgekom in die SUDI-gevalle en in die vergelykingsgroep. Gevolgtrekking: In gevalle met 'n OVD van SIDS, kan die virusse wat met PKR opgespoor is nie geïgnoreer word nie, veral nie as dit ondersteun word deur histologiese tekens van infeksie, soos waargeneem tydens hierdie studie nie. Die gebruik van real-time PKR analises het dus die vermoë om die verandering van ‘n OVD-klassifikasie van SIDS na Infeksie te ondersteun. Die rol van enkel- of veelvuldige infeksies met respiratoriese virusse in SUDI-gevalle waarin geen histologiese teken van infeksie waargeneem is nie, vereis egter verdere ondersoek. Meer navorsing is nodig om die rol van mede infeksies te ondersoek in SUDI gevalle, meer spesifiek die rol van virale interaksies in progressie en erns van siektes by 'n kwesbare baba. Laastens moet navorsing gerig wees op die bepaling van die effek van PKR-positiewe virale resultate in die afwesigheid van histologie om die werklike oorsaak van die kwesbaarheid van babas te identifiseer.

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