Trends in Cases, Hospitalizations, and Mortality Related to the Omicron BA.4/BA.5 Subvariants in South Africa.

BACKGROUND: In this study, we compared admission incidence risk and the risk of mortality in the Omicron BA.4/BA.5 wave to previous waves. METHODS: Data from South Africa's SARS-CoV-2 case linelist, national COVID-19 hospital surveillance system, and Electronic Vaccine Data System were linked and analyzed. Wave periods were defined when the country passed a weekly incidence of 30 cases/100 000 population. In-hospital case fatality ratios (CFRs) during the Delta, Omicron BA.1/BA.2, and Omicron BA.4/BA.5 waves were compared using post-imputation random effect multivariable logistic regression models. RESULTS: The CFR was 25.9% (N = 37 538 of 144 778), 10.9% (N = 6123 of 56 384), and 8.2% (N = 1212 of 14 879) in the Delta, Omicron BA.1/BA.2, and Omicron BA.4/BA.5 waves, respectively. After adjusting for age, sex, race, comorbidities, health sector, and province, compared with the Omicron BA.4/BA.5 wave, patients had higher risk of mortality in the Omicron BA.1/BA.2 wave (adjusted odds ratio [aOR], 1.3; 95% confidence interval [CI]: 1.2-1.4) and Delta wave (aOR, 3.0; 95% CI: 2.8-3.2). Being partially vaccinated (aOR, 0.9; 95% CI: .9-.9), fully vaccinated (aOR, 0.6; 95% CI: .6-.7), and boosted (aOR, 0.4; 95% CI: .4-.5) and having prior laboratory-confirmed infection (aOR, 0.4; 95% CI: .3-.4) were associated with reduced risks of mortality. CONCLUSIONS: Overall, admission incidence risk and in-hospital mortality, which had increased progressively in South Africa's first 3 waves, decreased in the fourth Omicron BA.1/BA.2 wave and declined even further in the fifth Omicron BA.4/BA.5 wave. Mortality risk was lower in those with natural infection and vaccination, declining further as the number of vaccine doses increased.

Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression.

BACKGROUND: Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination. METHODS: This study was designed as a systematic review and meta-regression. We did a systematic review of preprint and peer-reviewed published article databases from June 17, 2021, to Dec 2, 2021. Randomised controlled trials of COVID-19 vaccine efficacy and observational studies of COVID-19 vaccine effectiveness were eligible. Studies with vaccine efficacy or effectiveness estimates at discrete time intervals of people who had received full vaccination and that met predefined screening criteria underwent full-text review. We used random-effects meta-regression to estimate the average change in vaccine efficacy or effectiveness 1-6 months after full vaccination. FINDINGS: Of 13 744 studies screened, 310 underwent full-text review, and 18 studies were included (all studies were carried out before the omicron variant began to circulate widely). Risk of bias, established using the risk of bias 2 tool for randomised controlled trials or the risk of bias in non-randomised studies of interventions tool was low for three studies, moderate for eight studies, and serious for seven studies. We included 78 vaccine-specific vaccine efficacy or effectiveness evaluations (Pfizer-BioNTech-Comirnaty, n=38; Moderna-mRNA-1273, n=23; Janssen-Ad26.COV2.S, n=9; and AstraZeneca-Vaxzevria, n=8). On average, vaccine efficacy or effectiveness against SARS-CoV-2 infection decreased from 1 month to 6 months after full vaccination by 21·0 percentage points (95% CI 13·9-29·8) among people of all ages and 20·7 percentage points (10·2-36·6) among older people (as defined by each study, who were at least 50 years old). For symptomatic COVID-19 disease, vaccine efficacy or effectiveness decreased by 24·9 percentage points (95% CI 13·4-41·6) in people of all ages and 32·0 percentage points (11·0-69·0) in older people. For severe COVID-19 disease, vaccine efficacy or effectiveness decreased by 10·0 percentage points (95% CI 6·1-15·4) in people of all ages and 9·5 percentage points (5·7-14·6) in older people. Most (81%) vaccine efficacy or effectiveness estimates against severe disease remained greater than 70% over time. INTERPRETATION: COVID-19 vaccine efficacy or effectiveness against severe disease remained high, although it did decrease somewhat by 6 months after full vaccination. By contrast, vaccine efficacy or effectiveness against infection and symptomatic disease decreased approximately 20-30 percentage points by 6 months. The decrease in vaccine efficacy or effectiveness is likely caused by, at least in part, waning immunity, although an effect of bias cannot be ruled out. Evaluating vaccine efficacy or effectiveness beyond 6 months will be crucial for updating COVID-19 vaccine policy. FUNDING: Coalition for Epidemic Preparedness Innovations.

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study.

BACKGROUND: The SARS-CoV-2 omicron variant of concern was identified in South Africa in November, 2021, and was associated with an increase in COVID-19 cases. We aimed to assess the clinical severity of infections with the omicron variant using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy. METHODS: We did data linkages for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data. For individuals diagnosed with COVID-19 via TaqPath PCR tests, infections were designated as either SGTF or non-SGTF. The delta variant was identified by genome sequencing. Using multivariable logistic regression models, we assessed disease severity and hospitalisations by comparing individuals with SGTF versus non-SGTF infections diagnosed between Oct 1 and Nov 30, 2021, and we further assessed disease severity by comparing SGTF-infected individuals diagnosed between Oct 1 and Nov 30, 2021, with delta variant-infected individuals diagnosed between April 1 and Nov 9, 2021. FINDINGS: From Oct 1 (week 39), 2021, to Dec 6 (week 49), 2021, 161 328 cases of COVID-19 were reported in South Africa. 38 282 people were diagnosed via TaqPath PCR tests and 29 721 SGTF infections and 1412 non-SGTF infections were identified. The proportion of SGTF infections increased from two (3·2%) of 63 in week 39 to 21 978 (97·9%) of 22 455 in week 48. After controlling for factors associated with hospitalisation, individuals with SGTF infections had significantly lower odds of admission than did those with non-SGTF infections (256 [2·4%] of 10 547 vs 121 [12·8%] of 948; adjusted odds ratio [aOR] 0·2, 95% CI 0·1-0·3). After controlling for factors associated with disease severity, the odds of severe disease were similar between hospitalised individuals with SGTF versus non-SGTF infections (42 [21%] of 204 vs 45 [40%] of 113; aOR 0·7, 95% CI 0·3-1·4). Compared with individuals with earlier delta variant infections, SGTF-infected individuals had a significantly lower odds of severe disease (496 [62·5%] of 793 vs 57 [23·4%] of 244; aOR 0·3, 95% CI 0·2-0·5), after controlling for factors associated with disease severity. INTERPRETATION: Our early analyses suggest a significantly reduced odds of hospitalisation among individuals with SGTF versus non-SGTF infections diagnosed during the same time period. SGTF-infected individuals had a significantly reduced odds of severe disease compared with individuals infected earlier with the delta variant. Some of this reduced severity is probably a result of previous immunity. FUNDING: The South African Medical Research Council, the South African National Department of Health, US Centers for Disease Control and Prevention, the African Society of Laboratory Medicine, Africa Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Fleming Fund.

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study.

BACKGROUND: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]). INTERPRETATION: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. FUNDING: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

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.

In Utero Human Cytomegalovirus Infection Is Associated With Increased Levels of Putatively Protective Maternal Antibodies in Nonprimary Infection: Evidence for Boosting but Not Protection.

BACKGROUND: Although primary maternal cytomegalovirus infections are associated with higher risk of in utero transmission, most fetal infections worldwide result from nonprimary maternal infections. Antibodies directed at glycoprotein B (gB) and the gH/gL/pUL128-130-131 pentamer can neutralize virus, and higher levels of antibody directed at several particular pentamer epitopes defined by monoclonal antibodies (mAbs) are associated with reduced risk of fetal cytomegalovirus (CMV) transmission during primary maternal infection. This had not been explored in maternal nonprimary infection. METHODS: In a setting where most maternal CMV infections are nonprimary, 42 mothers of infants with congenital CMV infections (transmitters) were compared to 75 CMV-seropositive mothers whose infants were CMV-uninfected (nontransmitters). Control infants were matched by sex, maternal human immunodeficiency virus (HIV) status, and gestational age. We measured the ability of maternal antibodies to block 3 key pentameric epitopes: one in the gH subunit, another straddling UL130/UL131, and the third straddling gH/gL/UL128/UL130. We tested if levels of antibodies directed at these epitopes were higher in nontransmitters compared to transmitters. RESULTS: Levels of all 3 putatively protective pentamer-directed antibodies were significantly higher in transmitters compared to nontransmitters. In contrast, antibodies targeting an epitope on gB were not different. Total antibody specific for pentamer and for gB were also higher in transmitters. CONCLUSIONS: We found no evidence that higher levels of any CMV-specific antibodies were associated with reduced risk of congenital CMV infection in nonprimary maternal infection. Instead, we found higher maternal antibody targeting epitopes on CMV pentamer in transmitters than nontransmitters, providing evidence for antibody boosting but not protection.

Cytokine profiles in children with acute intussusception in South Africa.

Serum specimens of children hospitalized with acute intussusception (IS; n = 407) were analyzed for various pro- and anti-inflammatory cytokines to identify host markers specifically for IS compared to other surgical conditions (n = 235) or acute gastroenteritis (AGE; n = 68) in a cross-sectional study design. We showed that children with IS had elevated levels of pro-inflammatory cytokines IFN-γ, TNF-α, MIP-1ß, IL-1ß, IL-2, IL-6, IL-7, IL-8, and IL-17 as well as anti-inflammatory cytokines IL-1RA, IL-4, IL-5, and IL-13 compared to those admitted with surgical conditions or AGE symptoms, indicating these cytokines as markers for IS. In addition, we showed an increase in C-reactive protein (CRP) levels in children with IS. This study is the first to show a broad cytokine profile and identify cytokine markers in children with IS.

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 < 5 years, 5-15 years and > 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.

Clinical presentation and management of childhood intussusception in South Africa.

PURPOSE: We assessed management and outcomes for intussusception at nine academic hospitals in South Africa. METHODS: Patients ≤ 3 years presenting with intussusception between September 2013 and December 2017 were prospectively enrolled at all sites. Additionally, patients presenting between July 2012 and August 2013 were retrospectively enrolled at one site. Demographics, clinical information, diagnostic modality, reduction methods, surgical intervention and outcomes were reviewed. RESULTS: Four hundred seventy-six patients were enrolled, [54% males, median age 6.5 months (IQR 2.6-32.6)]. Vomiting (92%), bloody stool (91%), abdominal mass (57%), fever (32%) and a rectal mass (29%) represented advanced disease: median symptom duration was 3 days (IQR 1-4). Initial reduction attempts included pneumatic reduction (66%) and upfront surgery (32%). The overall non-surgical reduction rate was 28% and enema perforation rate was 4%. Surgery occurred in 334 (70%), 68 (20%) patients had perforated bowel, bowel resection was required in 61%. Complications included recurrence (2%) and nosocomial sepsis (4%). Length of stay (LOS) was significantly longer in patients who developed complications. Six patients died-a mortality rate of 1%. There was a significant difference in reduction rates, upfront surgery, bowel resection, LOS and mortality between centres with shorter symptom duration compared longer symptom duration. CONCLUSION: Delayed presentation was common and associated with low success for enema reduction, higher operative rates, higher rates of bowel resection and increased LOS. Improved primary health-care worker education and streamlining referral pathways might facilitate timely management.

Evaluation of Intussusception After Oral Monovalent Rotavirus Vaccination in South Africa.

BACKGROUND: Postlicensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix (RV1) administration, at 6 and 14 weeks of age, in an upper-middle-income country, South Africa. METHODS: Active prospective surveillance for intussusception was conducted in 8 hospitals from September 2013 through December 2017. Retrospective case enrollment was done at 1 hospital from July 2012 through August 2013. Demographic characteristics, symptom onset, and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence rate ratios within 1-7, 8-21, and 1-21 days of rotavirus vaccination in children aged 28-275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n = 169), and a secondary analysis was performed. RESULTS: Three hundred forty-six cases were included in the case-series analysis. Post-dose 1, there were zero intussusception cases within 1-7 days, and 5 cases within 8-21 days of vaccination. Post-dose 2, 15 cases occurred within 1-7 days, and 18 cases within 8-21 days of vaccination. There was no increased risk of intussusception 1-7 days after dose 1 (no cases observed) or dose 2 (relative incidence [RI], 1.71 [95% confidence interval {CI} .83-3.01]). Similarly, there was no increased risk 8-21 days after the first (RI, 4.01 [95% CI, .87-10.56]) or second dose (RI, .96 [95% CI, .52-1.60]). Results were similar for the case-control analysis. CONCLUSIONS: The risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants. CLINICAL TRIALS REGISTRATION: South African National Clinical Trial Register (DOH-27-0913-4183).

Prevalence of Congenital Cytomegalovirus Infection and Associated Risk of In Utero Human Immunodeficiency Virus (HIV) Acquisition in a High-HIV Prevalence Setting, South Africa.

BACKGROUND: There is a paucity of data on the burden of congenital cytomegalovirus (cCMV) infections in low- and middle-income countries, including their association with maternal human immunodeficiency virus (HIV) infections. We investigated the prevalence of cCMV in a patient population with a high rate of HIV and antiretroviral therapy (ART) use during pregnancy in Soweto, Johannesburg. METHODS: Saliva from neonates were screened for cytomegalovirus (CMV) infection by polymerase chain reaction (PCR) at birth. Additional saliva and urine samples were tested within 3 weeks of birth to confirm positive saliva results. HIV PCR testing was done on the whole blood of HIV-exposed neonates. Maternal and neonatal data were extracted from clinical records. RESULTS: Of 2685 neonates screened for cCMV, 828 (31%) were born to HIV-infected women, 95% of whom (790/828) were on ART at delivery. The overall prevalence of cCMV was 2.5% (95% confidence interval [CI] 1.9-3.2), with significantly higher cCMV prevalence in HIV-exposed neonates (5.2%, 95% CI 3.8-6.9) than HIV-unexposed neonates (1.4%, 95% CI 0.9-2.0). The risk of in utero HIV infection was 20-fold greater (odds ratio 20.1, 95% CI 6.09-66.46) in HIV-exposed, cCMV-infected neonates, and this increased risk was not associated with the maternal CD4+ T-cell count or the maternal duration of ART. CONCLUSIONS: The prevalence of cCMV in our setting is substantially higher than the global estimate of 0.64%, partly due to the increased susceptibility for cCMV in HIV-exposed neonates. The significantly increased risk of in utero HIV infection in neonates with cCMV indicates that CMV coinfection plays a major role in the residual burden of in utero HIV transmission, even in the era of ART.

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.

Severity of Respiratory Syncytial Virus Lower Respiratory Tract Infection With Viral Coinfection in HIV-Uninfected Children.

Background: Molecular diagnostics enable sensitive detection of respiratory viruses, but their clinical significance remains unclear in pediatric lower respiratory tract infection (LRTI). We aimed to determine whether viral coinfections increased life-threatening disease in a large cohort. Methods: Molecular testing was performed for respiratory viruses in nasopharyngeal aspirates collected from children aged <5 years within 24 hours of hospital admission during sentinel surveillance for severe acute respiratory illness (SARI) hospitalization conducted in South Africa during February 2009-December 2013. The primary outcome was life-threatening disease, defined as mechanical ventilation, intensive care unit admission, or death. Results: Of 2322 HIV-uninfected children with respiratory syncytial virus (RSV)-associated LRTI, 1330 (57.3%) had RSV monoinfection, 38 (1.6%) had life-threatening disease, 575 (24.8%) had rhinovirus, 347 (14.9%) had adenovirus (ADV), and 30 (1.3%) had influenza virus. RSV and any other viral coinfection was not associated with severe disease, ADV coinfection had increased odds of life-threatening disease (adjusted OR, 3.4; 95% CI, 1.6-7.2; P = .001), and influenza coinfection had increased odds of life-threatening disease and prolonged length of stay (adjusted OR, 2.1; 95% CI, 1.0-4.5; P = .05) compared with RSV monoinfection. Conclusions: RSV coinfection with any respiratory virus is not associated with more severe disease when compared to RSV alone in this study. However, increased life-threatening disease in RSV-ADV and RSV-influenza coinfection warrants further study.

Pneumococcal conjugate vaccines and hospitalization of children for pneumonia: a time-series analysis, South Africa, 2006-2014.

OBJECTIVE: To assess the impact of immunization with pneumococcal conjugate vaccines on all-cause pneumonia hospitalizations among children in Soweto, South Africa. METHODS: We used data collected at the Chris Hani Baragwanath Hospital in Soweto between 2006 and 2014 - i.e. before and after April 2009, when a pneumococcal conjugate vaccine was first included in South Africa's routine immunization programme. Using a Bayesian generalized seasonal autoregressive moving-average model and the data collected in 2006-2008, we estimated the numbers of children that would have been hospitalized for pneumonia between 2010 and 2014 if no pneumococcal conjugate vaccines had been used. These estimates were then compared with the corresponding numbers of hospitalizations observed. FINDINGS: Between 2006 and 2014, 26 778 children younger than five years - including 3388 known to be infected with human immunodeficiency virus (HIV) - were admitted to the study hospital for pneumonia. We estimated that, for the children known to be infected with HIV and for the other children, pneumococcal conjugate vaccines reduced the numbers of hospitalizations for pneumonia in 2014 by 33% (50% credible interval, CrI: 6 to 52) and 39% (50% CrI: 24 to 50), respectively. In the study hospital in 2012-2014, as a result of immunizations with these vaccines, there were an estimated 3100 fewer pneumonia hospitalizations of children younger than five years. CONCLUSION: In our study hospital, following the introduction of pneumococcal conjugate vaccines into the national immunization programme, there were significant reductions in pneumonia hospitalizations among children.

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.

Temporal Association of Rotavirus Vaccine Introduction and Reduction in All-Cause Childhood Diarrheal Hospitalizations in South Africa.

BACKGROUND: The public health impact of rotavirus vaccination in African settings with a high human immunodeficiency virus (HIV) infection prevalence is yet to be established. We evaluated trends in all-cause diarrheal hospitalizations in Soweto, Johannesburg, before and after the introduction of rotavirus vaccine into South Africa's national immunization program in August 2009. METHODS: Hospitalizations in children <5 years of age with a diagnosis of diarrhea, defined byInternational Classification of Diseases, Tenth Revisioncodes A00-A05, A06.0-A06.3, A06.9, A07.0-A07.2, A07.9, and A08-A09, were identified at the Chris Hani Baragwanath Academic Hospital from 1 January 2006 to 31 December 2014. The median annual prevaccine (2006-2008) hospitalization incidence was compared to that of the vaccine era (2010-2014), and stratified by age group and HIV infection status. RESULTS: Incidence reductions (per 1000 population) were greatest in children aged <12 months: 54.4 in the prevaccine era vs 30.0, 23.6, 20.0, 18.8, and 18.9 in the postvaccine years 2010-2014, respectively (a 44.9%-65.4% reduction). Lower incidence reductions (39.8%-49.4%) were observed among children aged 12-24 months from the second year post-vaccine introduction onward. Reductions were observed in both HIV-infected and HIV-uninfected children. There was a change in the seasonal pattern of diarrheal hospitalizations post-vaccine introduction, with flattening of the autumn-winter peaks seen in the prevaccine years. CONCLUSIONS: An accelerated and sustained decline in all-cause diarrheal hospitalizations, temporally associated with rotavirus vaccine introduction, was observed in children <2 years of age. However, the impact of other interventions such as improved sanitation and changes in HIV management cannot be discounted.

Prevaccination Rotavirus Serum IgG and IgA Are Associated With Lower Immunogenicity of Live, Oral Human Rotavirus Vaccine in South African Infants.

BACKGROUND: Live oral rotavirus (RV) vaccines have shown modest efficacy among children in African countries for reasons that are not completely understood. We examined the possible inhibitory effect of preexisting antirotavirus antibodies on immunogenicity of monovalent RV vaccine (RV1). METHODS: Mother-infant pairs were enrolled at presentation for their routine immunization visit in Soweto, South Africa, when infants were aged 5-8 weeks. Infant serum samples were obtained before the first and second doses of RV1 and 1 month after the second dose. Maternal serum and breast milk samples were obtained prior to administration of each dose of RV1 to infants. RV-specific immunoglobulin G (IgG), IgA, and neutralizing activity in sera of infants and serum or breast milk samples of mothers were measured using enzyme-linked immunosorbent assays or a microneutralization test. RESULTS: Of the 107 serum pairs from infants who were seronegative for RV IgA at enrollment, we observed a strong positive association between IgG titers in pre-dose 1 sera of infants and mothers and significant negative associations between IgG titers in pre-dose 1 sera of infants and seroconversion to RV1 post-dose 1. Similarly, mothers whose infants' IgA seroconverted after RV1 had significantly lower pre-dose 1 IgG titers in sera than those whose infants did not seroconvert. CONCLUSIONS: High levels of preexisting serum IgG, including transplacentally acquired maternal IgG, appeared to have an inhibitory effect on the immunogenicity of RV1 among infants and may, in part, contribute to lower efficacy of RV vaccines in this and other low-income settings.

Increased risk for group B Streptococcus sepsis in young infants exposed to HIV, Soweto, South Africa, 2004-2008(1).

Although group B Streptococcus (GBS) is a leading cause of severe invasive disease in young infants worldwide, epidemiologic data and knowledge about risk factors for the disease are lacking from low- to middle-income countries. To determine the epidemiology of invasive GBS disease among young infants in a setting with high maternal HIV infection, we conducted hospital-based surveillance during 2004-2008 in Soweto, South Africa. Overall GBS incidence was 2.72 cases/1,000 live births (1.50 and 1.22, respectively, among infants with early-onset disease [EOD] and late-onset [LOD] disease). Risk for EOD and LOD was higher for HIV-exposed than HIV-unexposed infants. GBS serotypes Ia and III accounted for 84.0% of cases, and 16.9% of infected infants died. We estimate that use of trivalent GBS vaccine (serotypes Ia, Ib, and III) could prevent 2,105 invasive GBS cases and 278 deaths annually among infants in South Africa; therefore, vaccination of all pregnant women in this country should be explored.