Diagnostic testing practices for diarrhoeal cases in South African public hospitals

BACKGROUND : Stool samples submitted for diagnostic testing represent a proportion of diarrhoeal cases seeking healthcare, and an even smaller proportion of diarrhoeal cases in the community. Despite this, surveillance relies heavily on these laboratory results. This study described diarrhoeal diagnostic practices and aetiological agents of diarrhoea in patients admitted to three South African public hospitals in order to understand biases in surveillance data, and inform guidelines, diagnostic and laboratory practices to improve clinical management. METHODS : A doctors’ survey was conducted to determine sample submission, diarrhoeal treatment and barriers to submitting samples for testing. Results for all samples submitted for routine diagnostics were obtained from the NHLS Central Data Warehouse. An enhanced surveillance study enrolled patients with acute diarrhoea at the same hospitals over the same period. Differences between routine culture results and molecular testing from the surveillance study were described. RESULTS : Stool samples were seldom submitted for diagnostic testing (median of 10% of admitted cases). Current diagnostic guidelines were not useful, hence most doctors (75.1%) relied on their own clinical judgement or judgement of a senior clinician. Although most doctors (90.3%) agreed that diagnostics were helpful for clinical management, they reported patients being unwilling to provide samples and long laboratory turnaround times. Routine diagnostic data represent cases with chronic diarrhoea and dysentery since doctors are most likely to submit specimens for these cases. Pathogen yield (number of pathogens detected for samples tested for specific pathogens) was significantly higher in the surveillance study, which used molecular methods, than through routine diagnostic services (73.3% versus 8.2%, p < 0.001), including for viruses (48.9% versus 2.6%, p < 0.001), bacteria (40.1% versus 2.2%, p < 0.001) and parasites (16.2% versus 3.6%, p < 0.001). Despite viruses being commonly detected in the surveillance study, viral testing was seldom requested in routine diagnostic investigations. CONCLUSIONS : Comprehensive diagnostic and treatment guidelines are required for diarrhoeal diseases. These guidelines should be informed by local epidemiological data, where diagnostic testing is reserved for cases most likely to benefit from specific treatment. Optimisation of current diagnostic processes and methods are required for these cases, specifically in terms of minimising turnaround times while maximising diagnostic acumen.The ANDEMIA study was supported by the German Federal Ministry of Education and Research.http://www.biomedcentral.com/bmcinfectdisam2023Medical VirologyPaediatrics and Child Healt

Identifying gaps in hand hygiene practice to support tailored target audience messaging in Soweto : a cross-sectional community survey

Effective risk communication is essential for outbreak mitigation, as recently highlighted during the coronavirus disease 2019 (COVID-19) pandemic. Hand hygiene is one of the proposed public health interventions to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) acquisition and transmission along with social distancing, improved ventilation, environmental cleaning, and wearing of masks. Improving hand hygiene practices in the community requires an understanding of the socio-behavioural context. This cross-sectional community survey in Soweto identified gaps in hand hygiene, which can inform appropriate messaging at the community level. Only 42% of survey respondents practiced adequate hand hygiene. Tailored educational messaging should be targeted at young adults in particular, and the importance of soap for hand hygiene must be emphasised for all age groups. Risk communication should expand to focus on preventing multiple infectious diseases during and beyond the COVID-19 pandemic.GlaxoSmithKline and the German Federal Ministry of Education and Research. The CHAMPS programme is funded by the Bill & Melinda Gates Foundation.https://sajid.co.za/index.php/sajiddm2022Medical Virolog

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series

Background: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. Methods: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms “RSV”, “respiratory syncytial virus”, or “respiratory syncytial viral” combined with “mortality”, “fatality”, “death”, “died”, “deaths”, or “CFR” for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. Findings: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3–11·0) in low-income or lower middle-income countries, 4·0 months (2·0–10·0) in upper middle-income countries, and 7·0 months (3·6–16·8) in high-income countries. Interpretation: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries

Epidemiology of human astroviruses among children younger than 5 years : prospective hospital‐based sentinel surveillance in South Africa, 2009‐2014

BACKGROUND : The epidemiology of human astroviruses (HAstVs) in hospitalised patients less than 5 years of age from selected sites in South Africa was investigated. Diarrheagenic stool specimens collected from April 2009 to May 2014 were screened retrospectively for selected viruses, bacteria and parasites. METHOD : Patient data were analysed to identify epidemiologic factors most frequently detected with HAstV infections. The following case‐comparisons were investigated; HAstV‐positive and HAstV‐negative children, human immunodeficiency virus (HIV)‐infected and HIV‐uninfected (HAstV‐positive) children and HIV‐exposed and unexposed (HAstV‐positive HIV‐uninfected) children. RESULTS : Astrovirus was identified in 7.0% (234/3340) of cases and most frequently in ages 7 to 12 months (9.2%; 90/975) compared with 5.8% to 6.6% in other 6‐month age groups. No seasonal trends were observed. More HAstVs were detected in children from homes that used outdoor water sources (7.6%) compared to indoor sources [5.7%; adjusted odds ratio (aOR), 1.5; 95% CI, 1.1‐2.1; P = 0.009]. Astroviruses were detected in 8.4% (67/799) of HIV‐uninfected patients that were exposed to HIV compared with 5.9% (74/1257) of HIV‐unexposed patients ( P = 0.032). CONCLUSION : Astroviruses were most prevalent in children aged 7 to 12 months and were detected throughout the study period. The study was limited as only hospitalised patients were investigated and no comparisons were made to diarrhoea‐free control groups. Future HAstV surveillance should include community‐based studies and children presenting at outpatient facilities.The Rotavirus Sentinel Surveillance Program was funded by GlaxoSmithKline (E‐Track 200238). Research was supported by a National Health Laboratory Service Research (004_94494) (SN) and the Poliomyelitis Research Foundation (15/22) (NAP).http://wileyonlinelibrary.com/journal/jmv2020-02-01hj2018Medical Virolog

Case-control vaccine effectiveness studies: Data collection, analysis and reporting results

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a \u27real world\u27 context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies

Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and control

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under \u27real world\u27 conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential

Diarrhoeal diseases in Soweto, South Africa, 2020 : a cross-sectional community survey

BACKGROUND : In South Africa, there are limited data on the burden of diarrhoea at a community level, specifically in older children and adults. This community survey estimated rates of and factors associated with diarrhoea across all ages and determined the proportion of cases presenting to healthcare facilities. METHODS : Households were enrolled from an existing urban health and demographic surveillance site. A household representative was interviewed to determine associated factors and occurrence of diarrhoea in the household, for all household members, in the past 2 weeks (including symptoms and health seeking behaviour). Diarrhoeal rate of any severity was calculated for 15 years age groups. Factors associated with diarrhoea and health seeking behaviour were investigated using binomial logistic regression. RESULTS : Diarrhoeal rate among respondents (2.5 episodes/person-year (95% CI, 1.8–3.5)) was significantly higher than for other household members (1.0 episodes/person-year (95% CI, 0.8–1.4); IRR = 2.4 (95% CI, 1.5–3.7) p < 0.001). Diarrhoeal rates were similar between age groups, however younger children (< 5 years) were more likely to present to healthcare facilities than adults (OR = 5.9 (95% CI, 1.1–31.4), p = 0.039). Oral rehydration solution was used in 44.8% of cases. Having a child between 5 and 15 years in the household was associated with diarrhoea (OR = 2.3 (95% CI, 1.3–3.9), p = 0.003) and, while 26.4% of cases sought healthcare, only 4.6% were hospitalised and only 3.4% of cases had a stool specimen collected. While the majority of cases were mild, 13.8% of cases felt they required healthcare but were unable to access it. CONCLUSION : Diarrhoeal rate was high across all age groups in this community; however, older children and adults were less likely to present to healthcare, and are therefore underrepresented through facility-based clinical surveillance. Current diarrhoeal surveillance represents a fraction of the overall cases occurring in the community.SUPPLEMENTARY MATERIAL: FIGURE S1. Health seeking for reported diarrhoeal episodes. TABLE S1. Factors associated with ORS knowledge.This work was supported by GlaxoSmithKline [E-Track 200238] and the German Federal Ministry of Education and Research [grant number 81203616] to SLJ. The CHAMPS program is funded by the Bill & Melinda Gates Foundation (Grant OPP1126780).http://www.biomedcentral.com/bmcpublichealtham2022Medical Virolog

Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa : a randomised, double-blind, placebo-controlled trial

BACKGROUND Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines. We assessed the safety and immunogenicity of the P2-VP8-P[8] subunit rotavirus vaccine at different doses in South African toddlers and infants. Methods This double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to <3 years) and term infants (aged 6 to <8 weeks, without previous rotavirus vaccination). Block randomisation (computer-generated, electronic allocation) was used to assign eligible toddlers (in a 6:1 ratio) and infants (in a 3:1 ratio) in each dose cohort (10 μg, followed by 30 μg, then 60 μg if doses tolerated) to parenteral P2-VP8-P[8] subunit rotavirus or placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P[8] vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P[8] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov, number NCT02109484. FINDINGS Between March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67–91) of 47 infants in the 30 μg group and 32 (68%, 53–81) of 47 in the 60 μg group, compared with nine (20%, 10–35) of 45 in the placebo group; adjusted IgG seroresponses were seen in 46 (98%, 89–100) of 47 infants in the 30 μg group and 47 (100%; 92–100) of 47 in the 60 μg group, compared with four (9%, 2·5–21) of 45 in the placebo group; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 (85%, 72–94) of 47 infants in both the 30 μg and 60 μg groups, compared with three (7%, 1·4–18) of 45 participants in the placebo group. Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo. Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups. Eight serious adverse events (one with placebo, two with 30 μg, and five with 60 μg) occurred in seven infants within 28 days of any study injection, none of which were deemed related to study treatment. INTERPRETATION The parenteral P2-VP8-P[8] vaccine was well tolerated and immunogenic in infants, providing a novel approach to vaccination against rotavirus disease. On the basis of these results, a phase 1/2 trial of a trivalent P2-VP8 (P[4], P[6], and P[8]) subunit vaccine is underway at three sites in South Africa.Bill & Melinda Gates Foundation.MJG reports funding from PATH Vaccine Solutions and personal fees from GlaxoSmithKline. AK and LJ report funding from PATH Vaccine Solutions. NP reports honoraria from GlaxoSmithKline, Merck, and Aspen Pharma. SAM reports grants from PATH, grants from Novartis and GlaxoSmithKline, and grants and personal fees from Pfizer and the Bill & Melinda Gates Foundation. MM reports laboratory service agreements with PATH, Merck, and GlaxoSmithKline. IC reports funding from PATH and is a paid consultant for PATH. MP is an employee of PATH, and reports grants from the Bill & Melinda Gates Foundation. AF, JF, LD, and SC declare no competing interests.http://www.thelancet.com/infectionam2017Medical Virolog

Development of a respiratory severity score for hospitalized adults in a high HIV-prevalence setting—South Africa, 2010-2011

BACKGROUND : Acute lower respiratory tract infections (LRTI) are a frequent cause of hospitalization and mortality in South Africa; however, existing respiratory severity scores may underestimate mortality risk in HIV-infected adults in resource limited settings. A simple predictive clinical score for low-resource settings could aid healthcare providers in the management of patients hospitalized with LRTI. METHODS : We analyzed 1,356 LRTI hospitalizations in adults aged ≥18 years enrolled in Severe Acute Respiratory Illness (SARI) surveillance in three South African hospitals from January 2010 to December 2011. Using demographic and clinical data at admission, we evaluated potential risk factors for in-hospital mortality. We evaluated three existing respiratory severity scores, CURB-65, CRB-65, and Classification Tree Analysis (CTA) Score assessing for discrimination and calibration. We then developed a new respiratory severity score using a multivariable logistic regression model for in-hospital mortality and assigned points to risk factors based on the coefficients in the multivariable model. Finally we evaluated the model statistically using bootstrap resampling techniques. RESULTS : Of the 1,356 patients hospitalized with LRTI, 101 (7.4%) died while hospitalized. The CURB-65, CRB-65, and CTA scores had poor calibration and demonstrated low discrimination with c-statistics of 0.594, 0.548, and 0.569 respectively. Significant risk factors for in-hospital mortality included age ≥ 45 years (A), confusion on admission (C), HIV-infection (H), and serum blood urea nitrogen >7 mmol/L (U), which were used to create the seven-point ACHU clinical predictor score. In-hospital mortality, stratified by ACHU score was: score ≤1, 2.4%, score 2, 6.4%, score 3, 11. 9%, and score ≥ 4, 29.3%. Final models showed good discrimination (c-statistic 0.789) and calibration (chi-square 1.6, Hosmer-Lemeshow goodness-of-fit p-value = 0.904) and discriminated well in the bootstrap sample (average optimism of 0.003). CONCLUSIONS : Existing clinical predictive scores underestimated mortality in a low resource setting with a high HIV burden. The ACHU score incorporates a simple set a risk factors that can accurately stratify patients ≥18 years of age with LRTI by in-hospital mortality risk. This score can quantify in-hospital mortality risk in an HIV-endemic, resource-limited setting with limited clinical information and if used to facilitate timely treatment may improve clinical outcomes.Additional file 1: BMC Pulmonary_Severity Score Data.xlsx. Severity Score Dataset. Dataset generated and used for analysis and creation of the ACHU score. Two tabs are included 1) includes the data used for the analysis 2) includes important notes related to the analytical methods and definitions for several composite variables.Additional file 2: Table S1. CURB-65, CRB-65, Classification Tree Analysis (CTA) severity scores. Table S2. Predicted and observed risk of mortality based on CURB-65, CRB-65, Classification Tree Analysis (CTA), and CURB-45 severity scores among hospitalized adults with lower respiratory tract infections, South Africa, 2010–2011. Table S3. Predicted and observed risk of mortality based by ACHU (Age, confusion, HIV, urea) respiratory severity score among hospitalized adults with lower respiratory tract infections, South Africa, 2010–2011.The Centers for Disease Control and Preventionhttp://www.biomedcentral.com/bmccom/plementalternmedam2017Medical Virolog

Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine : a multisite, randomised, double-blind, placebo-controlled trial

BACKGROUND : A monovalent, parenteral, subunit rotavirus vaccine was well tolerated and immunogenic in adults in the USA and in toddlers and infants in South Africa, but elicited poor responses against heterotypic rotavirus strains. We aimed to evaluate safety and immunogenicity of a trivalent vaccine formulation (P2-VP8-P[4],[6],[8]). METHODS : A double-blind, randomised, placebo-controlled, dose-escalation, phase 1/2 study was done at three South African research sites. Healthy adults (aged 18–45 years), toddlers (aged 2–3 years), and infants (aged 6–8 weeks, ≥37 weeks’ gestation, and without previous receipt of rotavirus vaccination), all without HIV infection, were eligible for enrolment. In the dose-escalation phase, adults and toddlers were randomly assigned in blocks (block size of five) to receive 30 μg or 90 μg of vaccine, or placebo, and infants were randomly assigned in blocks (block size of four) to receive 15 μg, 30 μg, or 90 μg of vaccine, or placebo. In the expanded phase, infants were randomly assigned in a 1:1:1:1 ratio to receive 15 μg, 30 μg, or 90 μg of vaccine, or placebo, in block sizes of four. Participants, parents of participants, and clinical, data, and laboratory staff were masked to treatment assignment. Adults received an intramuscular injection of vaccine or placebo in the deltoid muscle on the day of randomisation (day 0), day 28, and day 56; toddlers received a single injection of vaccine or placebo in the anterolateral thigh on day 0. Infants in both phases received an injection of vaccine or placebo in the anterolateral thigh on days 0, 28, and 56, at approximately 6, 10, and 14 weeks of age. Primary safety endpoints were local and systemic reactions (grade 2 or worse) within 7 days and adverse events and serious adverse events within 28 days after each injection in all participants who received at least one injection. Primary immunogenicity endpoints were analysed in infants in either phase who received all planned injections, had blood samples analysed at the relevant timepoints, and presented no major protocol violations considered to have an effect on the immunogenicity results of the study, and included serum anti-P2-VP8 IgA, IgG, and neutralising antibody geometric mean titres and responses measured 4 weeks after the final injection in vaccine compared with placebo groups. This trial is registered with ClinicalTrials.gov, NCT02646891. FINDINGS : Between Feb 15, 2016, and Dec 22, 2017, 30 adults (12 each in the 30 μg and 90 μg groups and six in the placebo group), 30 toddlers (12 each in the 30 μg and 90 μg groups and six in the placebo group), and 557 infants (139 in the 15 μg group, 140 in the 30 μg group, 139 in the 90 μg group, and 139 in the placebo group) were randomly assigned, received at least one dose, and were assessed for safety. There were no significant differences in local or systemic adverse events, or unsolicited adverse events, between vaccine and placebo groups. There were no serious adverse events within 28 days of injection in adults, whereas one serious adverse event occurred in a toddler (febrile convulsion in the 30 μg group) and 23 serious adverse events (four in placebo, ten in 15 μg, four in 30 μg, and five in 90 μg groups) occurred among 20 infants, most commonly respiratory tract infections. One death occurred in an infant within 28 days of injection due to pneumococcal meningitis. In 528 infants (130 in placebo, 132 in 15 μg, 132 in 30 μg, and 134 in 90 μg groups), adjusted anti-P2-VP8 IgG seroresponses (≥4-fold increase from baseline) to P[4], P[6], and P[8] antigens were significantly higher in the 15 μg, 30 μg, and 90 μg groups (99–100%) than in the placebo group (10–29%; p<0·0001). Although significantly higher than in placebo recipients (9–10%), anti-P2-VP8 IgA seroresponses (≥4-fold increase from baseline) to each individual antigen were modest (20–34%) across the 15 μg, 30 μg, and 90 μg groups. Adjusted neutralising antibody seroresponses in infants (≥2·7-fold increase from baseline) to DS-1 (P[4]), 1076 (P[6]), and Wa (P[8]) were higher in vaccine recipients than in placebo recipients: p<0·0001 for all comparisons. INTERPRETATION : The trivalent P2-VP8 vaccine was well tolerated, with promising anti-P2-VP8 IgG and neutralising antibody responses across the three vaccine P types. Our findings support advancing the vaccine to efficacy testing.The Bill and Melinda Gates Foundationhttp://www.thelancet.comam2020Medical Virolog