Incidence and transmission of respiratory syncytial virus in urban and rural South Africa, 2017-2018.

Data on respiratory syncytial virus (RSV) incidence and household transmission are limited. To describe RSV incidence and transmission, we conducted a prospective cohort study in rural and urban communities in South Africa over two seasons during 2017-2018. Nasopharyngeal swabs were collected twice-weekly for 10 months annually and tested for RSV using PCR. We tested 81,430 samples from 1,116 participants in 225 households (follow-up 90%). 32% (359/1116) of individuals had ≥1 RSV infection; 10% (37/359) had repeat infection during the same season, 33% (132/396) of infections were symptomatic, and 2% (9/396) sought medical care. Incidence was 47.2 infections/100 person-years and highest in children <5 years (78.3). Symptoms were commonest in individuals aged <12 and ≥65 years. Individuals 1-12 years accounted for 55% (134/242) of index cases. Household cumulative infection risk was 11%. On multivariable analysis, index cases with ≥2 symptoms and shedding duration >10 days were more likely to transmit; household contacts aged 1-4 years vs. ≥65 years were more likely to acquire infection. Within two South African communities, RSV attack rate was high, and most infections asymptomatic. Young children were more likely to introduce RSV into the home, and to be infected. Future studies should examine whether vaccines targeting children aged <12 years could reduce community transmission.

Incidence and Transmission Dynamics of Bordetella pertussis Infection in Rural and Urban Communities, South Africa, 2016‒2018.

We conducted 3 prospective cohort studies (2016-2018), enrolling persons from 2 communities in South Africa. Nasopharyngeal swab specimens were collected twice a week from participants. Factors associated with Bordetella pertussis incidence, episode duration, and household transmission were determined by using Poisson regression, Weibull accelerated time-failure, and logistic regression hierarchical models, respectively. Among 1,684 participants, 118 episodes of infection were detected in 107 participants (incidence 0.21, 95% CI 0.17-0.25 infections/100 person-weeks). Children <5 years of age who had incomplete vaccination were more likely to have pertussis infection. Episode duration was longer for participants who had higher bacterial loads. Transmission was more likely to occur from male index case-patients and persons who had >7 days infection duration. In both communities, there was high incidence of B. pertussis infection and most cases were colonized.

Unmasking Pneumococcal Carriage in a High Human Immunodeficiency Virus (HIV) Prevalence Population in two Community Cohorts in South Africa, 2016-2018: The PHIRST Study.

BACKGROUND: Longitudinal pneumococcus colonization data in high human immunodeficiency virus (HIV) prevalence settings following pneumococcal conjugate vaccine introduction are limited. METHODS: In 327 randomly selected households, 1684 individuals were enrolled and followed-up for 6 to 10 months during 2016 through 2018 from 2 communities. Nasopharyngeal swabs were collected twice weekly and tested for pneumococcus using quantitative lytA real-time polymerase chain reaction. A Markov model was fitted to the data to define the start and end of an episode of colonization. We assessed factors associated with colonization using logistic regression. RESULTS: During the study period, 98% (1655/1684) of participants were colonized with pneumococcus at least once. Younger age (<5 years: adjusted odds ratio [aOR], 14.1; 95% confidence [CI], 1.8-111.3, and 5-24 years: aOR, 4.8, 95% CI, 1.9-11.9, compared with 25-44 years) and HIV infection (aOR, 10.1; 95% CI, 1.3-77.1) were associated with increased odds of colonization. Children aged <5 years had fewer colonization episodes (median, 9) than individuals ≥5 years (median, 18; P < .001) but had a longer episode duration (<5 years: 35.5 days; interquartile range, 17-88) vs. ≥5 years: 5.5 days (4-12). High pneumococcal loads were associated with age (<1 year: aOR 25.4; 95% CI, 7.4-87.6; 1-4 years: aOR 13.5, 95% CI 8.3-22.9; 5-14 years: aOR 3.1, 95% CI, 2.1-4.4 vs. 45-65 year old patients) and HIV infection (aOR 1.7; 95% CI 1.2-2.4). CONCLUSIONS: We observed high levels of pneumococcus colonization across all age groups. Children and people with HIV were more likely to be colonized and had higher pneumococcal loads. Carriage duration decreased with age highlighting that children remain important in pneumococcal transmission.

Effectiveness of Influenza Vaccination of Pregnant Women for Prevention of Maternal and Early Infant Influenza-Associated Hospitalizations in South Africa: A Prospective Test-Negative Study.

Background: Influenza vaccination during pregnancy reduces influenza-associated illness in the women and their infants, but effectiveness estimates against influenza-associated hospitalization are limited and lacking from settings with high human immunodeficiency virus (HIV) infection prevalence. We assessed the effect of maternal vaccination in HIV-uninfected women and women with HIV in preventing influenza-associated hospitalizations in infants and the women. Methods: During 2015-2018, influenza vaccination campaigns targeting pregnant women were augmented at selected antenatal clinics; these were coupled with prospective hospital-based surveillance for acute respiratory or febrile illness in infants aged <6 months and cardiorespiratory illness among pregnant or postpartum women. Vaccine effectiveness (VE) was assessed using a test-negative case-control study. Results: Overall, 71 influenza-positive and 371 influenza-negative infants were included in the analysis; mothers of 26.8% of influenza-positive infants were vaccinated during pregnancy compared with 35.6% of influenza-negative infants, corresponding to an adjusted VE (aVE) of 29.0% (95% confidence interval [CI], -33.6% to 62.3%). When limited to vaccine-matched strains, aVE was 65.2% (95% CI, 11.7%-86.3%). For maternal hospitalizations, 56 influenza-positive and 345 influenza-negative women were included in the analysis, with 28.6% of influenza-positive women being vaccinated compared with 38.3% of influenza-negatives, for an aVE of 46.9% (95% CI, -2.8% to 72.5%). Analysis restricted to HIV-uninfected women resulted in 82.8% (95% CI, 40.7%-95.0%) aVE. No significant aVE (-32.5% [95% CI, -208.7% to 43.1%]) was detected among women with HIV. Conclusions: Influenza vaccination during pregnancy prevented influenza-associated hospitalizations among young infants when infected with vaccine strains and among HIV-uninfected women.

An evaluation of an influenza vaccination campaign targeting pregnant women in 27 clinics in two provinces of South Africa, 2015 - 2018.

INTRODUCTION: Despite prioritization, routine antenatal influenza vaccine coverage is < 16% in South Africa. We aimed to describe maternal influenza vaccine coverage in 27 antenatal clinics (ANCs) in Gauteng and Western Cape (WC) Provinces, where in collaboration with the Department of Health (DoH), we augmented the annual influenza vaccination programme among pregnant women. METHODS: From 2015 through 2018, 40,230 additional doses of influenza vaccine were added to the available stock and administered as part of routine antenatal care. Educational talks were given daily and data were collected on women attending ANCs. We compared characteristics of vaccinated and unvaccinated women using multivariable logistic regression. RESULTS: We screened 62,979 pregnant women during the period when Southern Hemisphere influenza vaccines were available (27,068 in Gauteng and 35,911 in WC). Vaccine coverage at the targeted clinics was 78.7% (49,355/62682), although pregnant women in WC were more likely to be vaccinated compared to those in the Gauteng (Odds ratio (OR) =3.7 p < 0.001). Women aged 25-29 and > 35 years were less likely to be vaccinated than women aged 18-24 years (OR = 0.9 p = 0.053; OR = 0.9 p < 0.001). HIV positive status was not associated with vaccination (OR = 1.0 p = 0.266). Reasons for not vaccinating included: vaccine stock-outs where ANCs depleted available stock of vaccines and/or were awaiting delivery of vaccines (54.6%, 6949/12723), refusal/indecision (25.8%, 3285), and current illness that contraindicated vaccination (19.6%, 2489). CONCLUSION: Antenatal vaccination uptake was likely improved by the increased vaccine supply and vaccine education offered during our campaign.

Epidemiology and Seasonality of Endemic Human Coronaviruses in South African and Zambian Children: A Case-Control Pneumonia Study.

Endemic human coronaviruses (HCoV) are capable of causing a range of diseases from the common cold to pneumonia. We evaluated the epidemiology and seasonality of endemic HCoVs in children hospitalized with clinical pneumonia and among community controls living in countries with a high HIV burden, namely South Africa and Zambia, between August 2011 to October 2013. Nasopharyngeal/oropharyngeal swabs were collected from all cases and controls and tested for endemic HCoV species and 12 other respiratory viruses using a multiplex real-time PCR assay. We found that the likelihood of detecting endemic HCoV species was higher among asymptomatic controls than cases (11% vs. 7.2%; 95% CI: 1.2-2.0). This was however only observed among children > 6 months and was mainly driven by the Betacoronavirus endemic species (HCoV-OC43 and -HKU1). Endemic HCoV species were detected through the year; however, in Zambia, the endemic Betacoronavirus species tended to peak during the winter months (May-August). There was no association between HIV status and endemic HCoV detection.

Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study.

Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1-59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3-1.6). This association was driven by the children aged 12-59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8-2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4-2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability (>75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing.

A cross-sectional study measuring contact patterns using diaries in an urban and a rural community in South Africa, 2018.

BACKGROUND: Describing contact patterns is crucial to understanding infectious disease transmission dynamics and guiding targeted transmission mitigation interventions. Data on contact patterns in Africa, especially South Africa, are limited. We measured and compared contact patterns in a rural and urban community, South Africa. We assessed participant and contact characteristics associated with differences in contact rates. METHODS: We conducted a cross-sectional study nested in a prospective household cohort study. We interviewed participants to collect information on persons in contact with for one day. We described self-reported contact rates as median number people contacted per day, assessed differences in contact rates based on participant characteristics using quantile regression, and used a Poisson model to assess differences in contact rates based on contact characteristics within age groups. We also calculated cumulative person hours in contact within age groups at different locations. RESULTS: We conducted 535 interviews (269 rural, 266 urban), with 17,252 contacts reported. The overall contact rate was 14 (interquartile range (IQR) 9-33) contacts per day. Those ≤18 years had higher contact rates at the rural site (coefficient 17, 95% confidence interval (95%CI) 10-23) compared to the urban site, for those aged 14-18 years (13, 95%CI 3-23) compared to < 7 years. No differences were observed for adults. There was a strong age-based mixing, with age groups interacting more with similar age groups, but also interaction of participants of all ages with adults. Children aged 14-18 years had the highest cumulative person hours in contact (116.3 rural and 76.4 urban). CONCLUSIONS: Age played an important role in the number and duration of contact events, with children at the rural site having almost double the contact rate compared to the urban site. These contact rates can be utilized in mathematical models to assess transmission dynamics of infectious diseases in similar communities.

Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017-18 (PHIRST): a population cohort study.

BACKGROUND: Data on influenza community burden and transmission are important to plan interventions especially in resource-limited settings. However, data are limited, particularly from low-income and middle-income countries. We aimed to evaluate the community burden and transmission of influenza in a rural and an urban setting in South Africa. METHODS: In this prospective cohort study approximately 50 households were selected sequentially from both a rural setting (Agincourt, Mpumalanga Province, South Africa; with a health and sociodemographic surveillance system) and an urban setting (Klerksdorp, Northwest Province, South Africa; using global positioning system data), enrolled, and followed up for 10 months in 2017 and 2018. Different households were enrolled in each year. Households of more than two individuals in which 80% or more of the occupants agreed to participate were included in the study. Nasopharyngeal swabs were collected twice per week from participating household members irrespective of symptoms and tested for influenza using real-time RT-PCR. The primary outcome was the incidence of influenza infection, defined as the number of real-time RT-PCR-positive episodes divided by the person-time under observation. Household cumulative infection risk (HCIR) was defined as the number of subsequent infections within a household following influenza introduction. FINDINGS: 81 430 nasopharyngeal samples were collected from 1116 participants in 225 households (follow-up rate 88%). 917 (1%) tested positive for influenza; 178 (79%) of 225 households had one or more influenza-positive individual. The incidence of influenza infection was 43·6 (95% CI 39·8-47·7) per 100 person-seasons. 69 (17%) of 408 individuals who had one influenza infection had a repeat influenza infection during the same season. The incidence (67·4 per 100 person-seasons) and proportion with repeat infections (22 [23%] of 97 children) were highest in children younger than 5 years and decreased with increasing age (p<0·0001). Overall, 268 (56%) of 478 infections were symptomatic and 66 (14%) of 478 infections were medically attended. The overall HCIR was 10% (109 of 1088 exposed household members infected [95% CI 9-13%). Transmission (HCIR) from index cases was highest in participants aged 1-4 years (16%; 40 of 252 exposed household members) and individuals with two or more symptoms (17%; 68 of 396 exposed household members). Individuals with asymptomatic influenza transmitted infection to 29 (6%) of 509 household contacts. HIV infection, affecting 167 (16%) of 1075 individuals, was not associated with increased incidence or HCIR. INTERPRETATION: Approximately half of influenza infections were symptomatic, with asymptomatic individuals transmitting influenza to 6% of household contacts. This suggests that strategies, such as quarantine and isolation, might be ineffective to control influenza. Vaccination of children, with the aim of reducing influenza transmission might be effective in African settings given the young population and high influenza burden. FUNDING: US Centers for Disease Control and Prevention.

A prospective case-control study on the association of Rhinovirus nasopharyngeal viral load and viremia in South African children hospitalized with severe pneumonia.

Rhinovirus (RV) role in pathogenesis of severe childhood disease remains controversial. We aimed to explore the association between RV molecular subtyping, nasopharyngeal viral loads and viremia with childhood pneumonia. Nasopharyngeal and blood samples from cases and controls were tested for RV and the 5' non-coding region sequenced. The cases compared to controls had a similar prevalence of RV detection in the nasopharynx (23 % vs. 22 %, P = 0.66), similar RV species distribution (A, B, C = 44 %, 8%, 44 % vs. 48 %, 7%, 38 %; respectively; P = 0.66) and similar viral load (4.0 and 3.7 log10 copies/mL, P = 0.062). However, RV-viremia was 4.01-fold (aOR 95 % CI: 1.26-12.78) more prevalent among cases (7%) than controls (2%), P = 0.019. Furthermore, among cases and controls RV-C was more commonly associated with viremia (14 % and 4%, P = 0.023), than RV-A (2% and 1%; P = 0.529). Thus RV-viremia could be used as a measure for attributing causality to RV in children hospitalized for pneumonia.

Potential of Minimally Invasive Tissue Sampling for Attributing Specific Causes of Childhood Deaths in South Africa: A Pilot, Epidemiological Study.

BACKGROUND: Current estimates for causes of childhood deaths are mainly premised on modeling of vital registration and limited verbal autopsy data and generally only characterize the underlying cause of death (CoD). We investigated the potential of minimally invasive tissue sampling (MITS) for ascertaining the underlying and immediate CoD in children 1 month to 14 years of age. METHODS: MITS included postmortem tissue biopsies of brain, liver, and lung for histopathology examination; microbial culture of blood, cerebrospinal fluid (CSF), liver, and lung samples; and molecular microbial testing on blood, CSF, lung, and rectal swabs. Each case was individually adjudicated for underlying, antecedent, and immediate CoD by an international multidisciplinary team of medical experts and coded using the International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: An underlying CoD was determined for 99% of 127 cases, leading causes being congenital malformations (18.9%), complications of prematurity (14.2%), human immunodeficiency virus/AIDS (12.6%), diarrheal disease (8.7%), acute respiratory infections (7.9%), injuries (7.9%), and malignancies (7.1%). The main immediate CoD was pneumonia, sepsis, and diarrhea in 33.9%, 19.7%, and 10.2% of cases, respectively. Infection-related deaths were either an underlying or immediate CoD in 78.0% of cases. Community-acquired pneumonia deaths (n = 32) were attributed to respiratory syncytial virus (21.9%), Pneumocystis jirovecii (18.8%), cytomegalovirus (15.6%), Klebsiella pneumoniae (15.6%), and Streptococcus pneumoniae (12.5%). Seventy-one percent of 24 sepsis deaths were hospital-acquired, mainly due to Acinetobacter baumannii (47.1%) and K. pneumoniae (35.3%). Sixty-two percent of cases were malnourished. CONCLUSIONS: MITS, coupled with antemortem clinical information, provides detailed insight into causes of childhood deaths that could be informative for prioritization of strategies aimed at reducing under-5 mortality.

An Observational Pilot Study Evaluating the Utility of Minimally Invasive Tissue Sampling to Determine the Cause of Stillbirths in South African Women.

BACKGROUND: Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting. METHODS: This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths. RESULTS: A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%). CONCLUSIONS: In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause.

Unraveling Specific Causes of Neonatal Mortality Using Minimally Invasive Tissue Sampling: An Observational Study.

BACKGROUND: Postmortem minimally invasive tissue sampling (MITS) is a potential alternative to the gold standard complete diagnostic autopsy for identifying specific causes of childhood deaths. We investigated the utility of MITS, interpreted with available clinical data, for attributing underlying and immediate causes of neonatal deaths. METHODS: This prospective, observational pilot study enrolled neonatal deaths at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. The MITS included needle core-biopsy sampling for histopathology of brain, lung, and liver tissue. Microbiological culture and/or molecular tests were performed on lung, liver, blood, cerebrospinal fluid, and stool samples. The "underlying" and "immediate" causes of death (CoD) were determined for each case by an international panel of 12-15 medical specialists. RESULTS: We enrolled 153 neonatal deaths, 106 aged 3-28 days. Leading underlying CoD included "complications of prematurity" (52.9%), "complications of intrapartum events" (15.0%), "congenital malformations" (13.1%), and "infection related" (9.8%). Overall, infections were the immediate or underlying CoD in 57.5% (n = 88) of all neonatal deaths, including the immediate CoD in 70.4% (58/81) of neonates with "complications of prematurity" as the underlying cause. Overall, 74.4% of 90 infection-related deaths were hospital acquired, mainly due to multidrug-resistant Acinetobacter baumannii (52.2%), Klebsiella pneumoniae (22.4%), and Staphylococcus aureus (20.9%). Streptococcus agalactiae was the most common pathogen (5/15 [33.3%]) among deaths with "infections" as the underlying cause. CONCLUSIONS: MITS has potential to address the knowledge gap on specific causes of neonatal mortality. In our setting, this included the hitherto underrecognized dominant role of hospital-acquired multidrug-resistant bacterial infections as the leading immediate cause of neonatal deaths.

Molecular Subtyping of Human Rhinovirus in Children from Three Sub-Saharan African Countries.

The pathogenesis of human rhinovirus (HRV) during severe respiratory disease remains undefined; thus, we aimed to explore the relationship between the HRV molecular subtyping results obtained during severe and asymptomatic childhood infections. Nasopharyngeal/oropharyngeal swabs from children (1 to 59 months of age) hospitalized with pneumonia and from age-frequency-matched controls were collected between August 2011 and August 2013. Swabs were tested for respiratory pathogens, including HRV, using quantitative real-time PCR assays. HRV-positive samples were sequenced for phylogenetic analysis by targeting the 5' noncoding region (5'NCR). Our data showed that there were no differences in the prevalence of HRV detection among cases and controls (21% versus 20%, P = 0.693); however, among children 13 to 59 months old, HRV detection was more often case associated (21% versus 16%; P = 0.009), with the results mainly driven by HRV-C (12% versus 7%; P = 0.001). Overall, there were no differences in the results of molecular subtyping of the HRV species prevalence among cases (for HRV-A, 48%; for HRV-B, 7%; for HRV-C, 45%) and controls (for HRV-A, 45%; for HRV-B, 10%; for HRV-C, 45% [P = 0.496]). Those with pneumonia and HRV-C were older (12.1 versus 9.4 months, P = 0.033) and more likely to present with wheeze (35% versus 25%, P = 0.031) than those with HRV-A cases. Thus, the rate of HRV detection was high, with similar degrees of genetic diversity among cases and controls, confounding the interpretation of the presence of HRV in nasopharyngeal samples for attribution of a causal role in the pathogenesis of severe pneumonia in infants. However, among children 13 to 59 months of age, HRV detection, in particular, HRV-C detection, was associated with case status, especially among children with wheezing disease.