Impact of Subgroup Distribution on Seasonality of Human Respiratory Syncytial Virus: A Global Systematic Analysis.

BACKGROUND: Previous studies reported inconsistent findings regarding the association between respiratory syncytial virus (RSV) subgroup distribution and timing of RSV season. We aimed to further understand the association by conducting a global-level systematic analysis. METHODS: We compiled published data on RSV seasonality through a systematic literature review, and unpublished data shared by international collaborators. Using annual cumulative proportion (ACP) of RSV-positive cases, we defined RSV season onset and offset as ACP reaching 10% and 90%, respectively. Linear regression models accounting for meteorological factors were constructed to analyze the association of proportion of RSV-A with the corresponding RSV season onset and offset. RESULTS: We included 36 study sites from 20 countries, providing data for 179 study-years in 1995-2019. Globally, RSV subgroup distribution was not significantly associated with RSV season onset or offset globally, except for RSV season offset in the tropics in 1 model, possibly by chance. Models that included RSV subgroup distribution and meteorological factors explained only 2%-4% of the variations in timing of RSV season. CONCLUSIONS: Year-on-year variations in RSV season onset and offset are not well explained by RSV subgroup distribution or meteorological factors. Factors including population susceptibility, mobility, and viral interference should be examined in future studies.

Characteristics of infections with ancestral, Beta and Delta variants of SARS-CoV-2 in the PHIRST-C community cohort study, South Africa, 2020-2021.

BACKGROUND: Data on the characteristics of individuals with mild and asymptomatic infections with different SARS-CoV-2 variants are limited. We therefore compared the characteristics of individuals infected with ancestral, Beta and Delta SARS-CoV-2 variants in South Africa. METHODS: We conducted a prospective cohort study in a rural and an urban site during July 2020-August 2021. Mid-turbinate nasal swabs were collected twice-weekly from household members irrespective of symptoms and tested for SARS-CoV-2 using real-time reverse transcription polymerase chain reaction (rRT-PCR). Differences in demographic and clinical characteristics, shedding and cycle threshold (Ct) value of infection episodes by variant were evaluated using multinomial regression. Overall and age-specific incidence rates of infection were compared by variant. RESULTS: We included 1200 individuals from 222 households and 648 rRT-PCR-confirmed infection episodes (66, 10% ancestral, 260, 40% Beta, 322, 50% Delta). Symptomatic proportion was similar for ancestral (7, 11%), Beta (44, 17%), and Delta (46, 14%) infections (p=0.4). After accounting for previous infection, peak incidence shifted to younger age groups in successive waves (40-59 years ancestral, 19-39 years Beta, 13-18 years Delta). On multivariable analysis, compared to ancestral, Beta infection was more common in individuals aged 5-12 years (vs 19-39)(adjusted odds ratio (aOR) 2.6, 95% confidence interval (CI)1.1-6.6) and PCR cycle threshold (Ct) value <30 (vs >35)(aOR 3.2, 95%CI 1.3-7.9), while Delta was more common in individuals aged <5 (aOR 6.7, 95%CI1.4-31.2) and 5-12 years (aOR 6.6 95%CI2.6-16.7)(vs 19-39) and Ct value <30 (aOR 4.5, 95%CI 1.3-15.5) and 30-35 (aOR 6.0, 95%CI 2.3-15.7)(vs >35). CONCLUSIONS: Consecutive SARS-CoV-2 waves with Beta and Delta variants were associated with a shift to younger individuals. Beta and Delta infections were associated with higher peak viral loads, potentially increasing infectiousness.

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.

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.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

The burden of RSV-associated illness in children aged < 5 years, South Africa, 2011 to 2016.

BACKGROUND: Vaccines and monoclonal antibodies to protect the very young infant against the respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost-effectiveness analyses. METHODS: We combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged < 5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the < 1-year age group, by 3-month intervals until 2 years, and then 12 monthly intervals to < 5 years for medically and non-medically attended illness. RESULTS: We estimated a mean annual total (medically and non-medically attended) of 264,112 (95% confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) cases of RSV-associated SARI (4.7% and 1.7% of the population aged < 5 years, respectively). RSV-associated ARI incidence was highest in 2-month-old infants (18,361/100,000 population, 95% CI 9336-28,466). The highest incidence of RSV-associated SARI was in the < 1-month age group 14,674/100,000 (95% CI 11,175-19,645). RSV-associated deaths were highest in the first and second month of life (110.8 (95% CI 74.8-144.5) and 111.3 (86.0-135.8), respectively). CONCLUSIONS: Due to the high burden of RSV-associated illness, specifically SARI cases in young infants, maternal vaccination and monoclonal antibody products delivered at birth could prevent significant RSV-associated disease burden.

Estimating the cost-effectiveness of maternal vaccination and monoclonal antibodies for respiratory syncytial virus in Kenya and South Africa.

BACKGROUND: Respiratory syncytial virus (RSV) causes a substantial burden of acute lower respiratory infection in children under 5 years, particularly in low- and middle-income countries (LMICs). Maternal vaccine (MV) and next-generation monoclonal antibody (mAb) candidates have been shown to reduce RSV disease in infants in phase 3 clinical trials. The cost-effectiveness of these biologics has been estimated using disease burden data from global meta-analyses, but these are sensitive to the detailed age breakdown of paediatric RSV disease, for which there have previously been limited data. METHODS: We use original hospital-based incidence data from South Africa (ZAF) and Kenya (KEN) collected between 2010 and 2018 of RSV-associated acute respiratory infection (ARI), influenza-like illness (ILI), and severe acute respiratory infection (SARI) as well as deaths with monthly age-stratification, supplemented with data on healthcare-seeking behaviour and costs to the healthcare system and households. We estimated the incremental cost per DALY averted (incremental cost-effectiveness ratio or ICER) of public health interventions by MV or mAb for a plausible range of prices (5-50 USD for MV, 10-125 USD for mAb), using an adjusted version of a previously published health economic model of RSV immunisation. RESULTS: Our data show higher disease incidence for infants younger than 6 months of age in the case of Kenya and South Africa than suggested by earlier projections from community incidence-based meta-analyses of LMIC data. Since MV and mAb provide protection for these youngest age groups, this leads to a substantially larger reduction of disease burden and, therefore, more favourable cost-effectiveness of both interventions in both countries. Using the latest efficacy data and inferred coverage levels based on antenatal care (ANC-3) coverage (KEN: 61.7%, ZAF: 75.2%), our median estimate of the reduction in RSV-associated deaths in children under 5 years in Kenya is 10.5% (95% CI: 7.9, 13.3) for MV and 13.5% (10.7, 16.4) for mAb, while in South Africa, it is 27.4% (21.6, 32.3) and 37.9% (32.3, 43.0), respectively. Starting from a dose price of 5 USD, in Kenya, net cost (for the healthcare system) per (undiscounted) DALY averted for MV is 179 (126, 267) USD, rising to 1512 (1166, 2070) USD at 30 USD per dose; for mAb, it is 684 (543, 895) USD at 20 USD per dose and 1496 (1203, 1934) USD at 40 USD per dose. In South Africa, a MV at 5 USD per dose would be net cost-saving for the healthcare system and net cost per DALY averted is still below the ZAF's GDP per capita at 40 USD dose price (median: 2350, 95% CI: 1720, 3346). For mAb in ZAF, net cost per DALY averted is 247 (46, 510) USD at 20 USD per dose, rising to 2028 (1565, 2638) USD at 50 USD per dose and to 6481 (5364, 7959) USD at 125 USD per dose. CONCLUSIONS: Incorporation of new data indicating the disease burden is highly concentrated in the first 6 months of life in two African settings suggests that interventions against RSV disease may be more cost-effective than previously estimated.

Transient increased risk of influenza infection following RSV infection in South Africa: findings from the PHIRST study, South Africa, 2016-2018.

BACKGROUND: Large-scale prevention of respiratory syncytial virus (RSV) infection may have ecological consequences for co-circulating pathogens, including influenza. We assessed if and for how long RSV infection alters the risk for subsequent influenza infection. METHODS: We analysed a prospective longitudinal cohort study conducted in South Africa between 2016 and 2018. For participating households, nasopharyngeal samples were taken twice weekly, irrespective of symptoms, across three respiratory virus seasons, and real-time polymerase chain reaction (PCR) was used to identify infection with RSV and/or influenza. We fitted an individual-level hidden Markov transmission model in order to estimate RSV and influenza infection rates and their interdependence. RESULTS: Of a total of 122,113 samples collected, 1265 (1.0%) were positive for influenza and 1002 (0.8%) positive for RSV, with 15 (0.01%) samples from 12 individuals positive for both influenza and RSV. We observed a 2.25-fold higher incidence of co-infection than expected if assuming infections were unrelated. We estimated that infection with influenza is 2.13 (95% CI 0.97-4.69) times more likely when already infected with, and for a week following, RSV infection, adjusted for age. This equates to 1.4% of influenza infections that may be attributable to RSV in this population. Due to the local seasonality (RSV season precedes the influenza season), we were unable to estimate changes in RSV infection risk following influenza infection. CONCLUSIONS: We find no evidence to suggest that RSV was associated with a subsequent reduced risk of influenza infection. Instead, we observed an increased risk for influenza infection for a short period after infection. However, the impact on population-level transmission dynamics of this individual-level synergistic effect was not measurable in this setting.

The economic burden of RSV-associated illness in children aged < 5 years, South Africa 2011-2016.

BACKGROUND: Data on the economic burden of RSV-associated illness will inform decisions on the programmatic implementation of maternal vaccines and monoclonal antibodies. We estimated the cost of RSV-associated illness in fine age bands to allow more accurate cost-effectiveness models to account for a limited duration of protection conferred by short- or long-acting interventions. METHODS: We conducted a costing study at sentinel sites across South Africa to estimate out-of-pocket and indirect costs for RSV-associated mild and severe illness. We collected facility-specific costs for staffing, equipment, services, diagnostic tests, and treatment. Using case-based data we calculated a patient day equivalent (PDE) for RSV-associated hospitalizations or clinic visits; the PDE was multiplied by the number of days of care to provide a case cost to the healthcare system. We estimated the costs in 3-month age intervals in children aged < 1 year and as a single group for children aged 1-4 years. We then applied our data to a modified version of the World Health Organization tool for estimating the mean annual national cost burden, including medically and non-medically attended RSV-associated illness. RESULTS: The estimated mean annual cost of RSV-associated illness in children aged < 5 years was US dollars ($)137,204,393, of which 76% ($111,742,713) were healthcare system incurred, 6% ($8,881,612) were out-of-pocket expenses and 13% ($28,225,.801) were indirect costs. Thirty-three percent ($45,652,677/$137,204,393) of the total cost in children aged < 5 years was in the < 3-month age group, of which 52% ($71,654,002/$137,204,393) were healthcare system incurred. The costs of non-medically attended cases increased with age from $3,307,218 in the < 3-month age group to $8,603,377 in the 9-11-month age group. CONCLUSIONS: Among children < 5 years of age with RSV in South Africa, the highest cost burden was in the youngest infants; therefore, interventions against RSV targeting this age group are important to reduce the health and cost burden of RSV-associated illness.

Prolonged Shedding of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at High Viral Loads Among Hospitalized Immunocompromised Persons Living With Human Immunodeficiency Virus (HIV), South Africa.

BACKGROUND: We assessed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding duration and magnitude among persons living with human immunodeficiency virus (HIV, PLHIV). METHODS: From May through December 2020, we conducted a prospective cohort study at 20 hospitals in South Africa. Adults hospitalized with symptomatic coronavirus disease 2019 (COVID-19) were enrolled and followed every 2 days with nasopharyngeal/oropharyngeal (NP/OP) swabs until documentation of cessation of SARS-CoV-2 shedding (2 consecutive negative NP/OP swabs). Real-time reverse transcription-polymerase chain reaction testing for SARS-CoV-2 was performed, and cycle-threshold (Ct) values < 30 were considered a proxy for high SARS-CoV-2 viral load. Factors associated with prolonged shedding were assessed using accelerated time-failure Weibull regression models. RESULTS: Of 2175 COVID-19 patients screened, 300 were enrolled, and 257 individuals (155 HIV-uninfected and 102 PLHIV) had > 1 swabbing visit (median 5 visits [range 2-21]). Median time to cessation of shedding was 13 days (interquartile range [IQR] 6-25) and did not differ significantly by HIV infection. Among a subset of 94 patients (41 PLHIV and 53 HIV-uninfected) with initial respiratory sample Ct-value < 30, median time of shedding at high SARS-CoV-2 viral load was 8 days (IQR 4-17). This was significantly longer in PLHIV with CD4 count < 200 cells/µL, compared to HIV-uninfected persons (median 27 days [IQR 8-43] vs 7 days [IQR 4-13]; adjusted hazard ratio [aHR] 0.14, 95% confidence interval [CI] .07-.28, P < .001), as well as in unsuppressed-HIV versus HIV-uninfected persons. CONCLUSIONS: Although SARS-CoV-2 shedding duration did not differ significantly by HIV infection, among a subset with high initial SARS-CoV-2 viral loads, immunocompromised PLHIV shed SARS-CoV-2 at high viral loads for longer than HIV-uninfected persons. Better HIV control may potentially decrease transmission time of SARS-CoV-2.

Seroprevalence of Severe Acute Respiratory Syndrome Coronavirus 2 After the Second Wave in South Africa in Human Immunodeficiency Virus-Infected and Uninfected Persons: A Cross-Sectional Household Survey.

BACKGROUND: Seroprevalence studies are important for quantifying the burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in resource-constrained countries. METHODS: We conducted a cross-sectional household survey spanning the second pandemic wave (November 2020 to April 2021) in 3 communities. Blood was collected for SARS-CoV-2 antibody (2 enzyme-linked immunosorbent assays targeting spike and nucleocapsid) and human immunodeficiency virus (HIV) testing. An individual was considered seropositive if testing positive on ≥1 assay. Factors associated with infection, and the age-standardized infection case detection rate, infection hospitalization rate, and infection fatality rate were calculated. RESULTS: Overall, 7959 participants were enrolled, with a median age of 34 years and an HIV prevalence of 22.7%. SARS-CoV-2 seroprevalence was 45.2% (95% confidence interval 43.7%-46.7%) and increased from 26.9% among individuals enrolled in December 2020 to 47.1% among those enrolled in April 2021. On multivariable analysis, seropositivity was associated with age, sex, race, being overweight/obese, having respiratory symptoms, and low socioeconomic status. Persons living with HIV with high viral load were less likely to be seropositive than HIV-uninfected individuals. The site-specific infection case detection rate, infection hospitalization rate, and infection fatality rate ranged across sites from 4.4% to 8.2%, 1.2% to 2.5%, and 0.3% to 0.6%, respectively. CONCLUSIONS: South Africa has experienced a large burden of SARS-CoV-2 infections, with <10% of infections diagnosed. Lower seroprevalence among persons living with HIV who are not virally suppressed, likely as a result of inadequate antibody production, highlights the need to prioritize this group for intervention.

SARS-CoV-2 Seroprevalence after Third Wave of Infections, South Africa.

By November 2021, after the third wave of severe acute respiratory syndrome coronavirus 2 infections in South Africa, seroprevalence was 60% in a rural community and 70% in an urban community. High seroprevalence before the Omicron variant emerged may have contributed to reduced illness severity observed in the fourth wave.

Estimating the contribution of HIV-infected adults to household pneumococcal transmission in South Africa, 2016-2018: A hidden Markov modelling study.

Human immunodeficiency virus (HIV) infected adults are at a higher risk of pneumococcal colonisation and disease, even while receiving antiretroviral therapy (ART). To help evaluate potential indirect effects of vaccination of HIV-infected adults, we assessed whether HIV-infected adults disproportionately contribute to household transmission of pneumococci. We constructed a hidden Markov model to capture the dynamics of pneumococcal carriage acquisition and clearance observed during a longitudinal household-based nasopharyngeal swabbing study, while accounting for sample misclassifications. Households were followed-up twice weekly for approximately 10 months each year during a three-year study period for nasopharyngeal carriage detection via real-time PCR. We estimated the effect of participant's age, HIV status, presence of a HIV-infected adult within the household and other covariates on pneumococcal acquisition and clearance probabilities. Of 1,684 individuals enrolled, 279 (16.6%) were younger children (<5 years-old) of whom 4 (1.5%) were HIV-infected and 726 (43.1%) were adults (≥18 years-old) of whom 214 (30.4%) were HIV-infected, most (173, 81.2%) with high CD4+ count. The observed range of pneumococcal carriage prevalence across visits was substantially higher in younger children (56.9-80.5%) than older children (5-17 years-old) (31.7-50.0%) or adults (11.5-23.5%). We estimate that 14.4% (95% Confidence Interval [CI]: 13.7-15.0) of pneumococcal-negative swabs were false negatives. Daily carriage acquisition probabilities among HIV-uninfected younger children were similar in households with and without HIV-infected adults (hazard ratio: 0.95, 95%CI: 0.91-1.01). Longer average carriage duration (11.4 days, 95%CI: 10.2-12.8 vs 6.0 days, 95%CI: 5.6-6.3) and higher median carriage density (622 genome equivalents per millilitre, 95%CI: 507-714 vs 389, 95%CI: 311.1-435.5) were estimated in HIV-infected vs HIV-uninfected adults. The use of ART and antibiotics substantially reduced carriage duration in all age groups, and acquisition rates increased with household size. Although South African HIV-infected adults on ART have longer carriage duration and density than their HIV-uninfected counterparts, they show similar patterns of pneumococcal acquisition and onward transmission.

SARS-CoV-2 Seroprevalence in a Rural and Urban Household Cohort during First and Second Waves of Infections, South Africa, July 2020-March 2021.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections may be underestimated because of limited access to testing. We measured SARS-CoV-2 seroprevalence in South Africa every 2 months during July 2020-March 2021 in randomly selected household cohorts in 2 communities. We compared seroprevalence to reported laboratory-confirmed infections, hospitalizations, and deaths to calculate infection-case, infection-hospitalization, and infection-fatality ratios in 2 waves of infection. Post-second wave seroprevalence ranged from 18% in the rural community children <5 years of age, to 59% in urban community adults 35-59 years of age. The second wave saw a shift in age distribution of case-patients in the urban community (from persons 35-59 years of age to persons at the extremes of age), higher attack rates in the rural community, and a higher infection-fatality ratio in the urban community. Approximately 95% of SARS-CoV-2 infections were not reported to national surveillance.

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.

Decline of influenza and respiratory syncytial virus detection in facility-based surveillance during the COVID-19 pandemic, South Africa, January to October 2020.

BackgroundIn South Africa, COVID-19 control measures to prevent SARS-CoV-2 spread were initiated on 16 March 2020. Such measures may also impact the spread of other pathogens, including influenza virus and respiratory syncytial virus (RSV) with implications for future annual epidemics and expectations for the subsequent northern hemisphere winter.MethodsWe assessed the detection of influenza and RSV through facility-based syndromic surveillance of adults and children with mild or severe respiratory illness in South Africa from January to October 2020, and compared this with surveillance data from 2013 to 2019.ResultsFacility-based surveillance revealed a decline in influenza virus detection during the regular season compared with previous years. This was observed throughout the implementation of COVID-19 control measures. RSV detection decreased soon after the most stringent COVID-19 control measures commenced; however, an increase in RSV detection was observed after the typical season, following the re-opening of schools and the easing of measures.ConclusionCOVID-19 non-pharmaceutical interventions led to reduced circulation of influenza and RSV in South Africa. This has limited the country's ability to provide influenza virus strains for the selection of the annual influenza vaccine. Delayed increases in RSV case numbers may reflect the easing of COVID-19 control measures. An increase in influenza virus detection was not observed, suggesting that the measures may have impacted the two pathogens differently. The impact that lowered and/or delayed influenza and RSV circulation in 2020 will have on the intensity and severity of subsequent annual epidemics is unknown and warrants close monitoring.

The Fraction of Rhinovirus Detections Attributable to Mild and Severe Respiratory Illness in a Setting of High Human Immunodeficiency Virus Prevalence, South Africa, 2013-2015.

BACKGROUND: The association of rhinovirus (RV) detection to illness is poorly understood. METHODS: We enrolled case patients hospitalized with severe respiratory illness (SRI) at 2 hospitals and outpatients with influenza-like illness (ILI) and asymptomatic individuals (controls) from 2 affiliated clinics during 2013-2015. We compared the RV prevalence among ILI and SRI cases to those of controls stratified by human immunodeficiency virus (HIV) serostatus using penalized logistic regression. The attributable fraction (AF) was calculated. RESULTS: During 2013-2015, RV was detected in 17.4% (368/2120), 26.8% (979/3654), and 23.0% (1003/4360) of controls, ILI cases, and SRI cases, respectively. The RV AF (95% confidence interval) was statistically significant among children aged <5 years (ILI: 44.6% [30.7%-55.7%] and SRI: 50.3% [38.6%-59.9%]; P < .001) and individuals aged ≥5 years (ILI: 62.9% [54.4%-69.8%] and SRI: 51.3% [38.7%-61.3%]; P < .001) as well as among HIV-infected (ILI: 59.9% [45.8%-70.3%] and SRI: 39.8% [22.3%-53.3%]; P < .001) and HIV-uninfected (ILI: 53.6% [44.7%-61.1%] and SRI: 55.3% [45.6%-63.2%]; P < .001) individuals. CONCLUSIONS: Although RV detection was common among controls, it was also associated with a substantial proportion of clinical illness across age groups, irrespective of HIV status.

The Impact of Human Immunodeficiency Virus Exposure on Respiratory Syncytial Virus-associated Severe Respiratory Illness in South African Infants, 2011-2016.

From 2011 through 2016, we conducted surveillance for severe respiratory illness in infants. Human immunodeficiency virus exposure significantly increased the risk of respiratory syncytial virus (RSV)-associated hospitalization in infants aged <5 months. More than 60% of RSV-associated hospitalizations occurred in the first 4 months of life and may be preventable through maternal vaccination or birth-dose monoclonal antibody.

The Role of Human Immunodeficiency Virus in Influenza- and Respiratory Syncytial Virus-associated Hospitalizations in South African Children, 2011-2016.

BACKGROUND: Data describing influenza- or respiratory syncytial virus (RSV)-associated hospitalized illness in children aged <5 years in Africa are limited. METHODS: During 2011-2016, we conducted surveillance for severe respiratory illness (SRI) in children aged <5 years in 3 South African hospitals. Nasopharyngeal aspirates were tested for influenza and RSV using real-time reverse transcription polymerase chain reaction. We estimated rates of influenza- and RSV-associated hospitalized SRI by human immunodeficiency virus (HIV) status and compared children who tested positive for influenza vs RSV using multivariable penalized logistic regression. RESULTS: Among 3650 hospitalized children, 203 (5.6%) tested positive for influenza viruses, 874 (23.9%) for RSV, and 19 (0.5%) for both. The median age of children hospitalized with influenza was 13.9 months vs 4.4 months for RSV (P < .01). Annual influenza-associated hospitalization rates per 100000 were highest among infants aged 6-11 months (545; 95% confidence interval [CI], 409-703), while RSV-associated hospitalization rates were highest in infants aged 0-2 months (6593; 95% CI, 5947-7217). HIV exposure was associated with increased incidence of influenza- and RSV-associated hospitalization in infants aged 0-5 months, with relative risk (RR) 2.2 (95% CI, 1.4-3.4) and 1.4 (95% CI, 1.3-1.6), respectively. HIV infection was associated with increased incidence of influenza- and RSV-associated hospitalization in all age groups; RR 2.7 (95% CI, 2.0-3.5) and 3.8 (95% CI, 3.1-4.8), respectively. CONCLUSIONS: Influenza- and RSV-associated hospitalizations are common among South African infants. HIV infection and HIV exposure in infants increase risk of influenza- and RSV-associated hospitalization.

Quantifying How Different Clinical Presentations, Levels of Severity, and Healthcare Attendance Shape the Burden of Influenza-associated Illness: A Modeling Study From South Africa.

BACKGROUND: Burden estimates of medically and nonmedically attended influenza-associated illness across syndromes and levels of severity are lacking. METHODS: We estimated the national burden of medically and nonmedically attended influenza-associated illness among individuals with different clinical presentations (all-respiratory, all-circulatory, and nonrespiratory/noncirculatory) and levels of severity (mild, fatal, and severe, nonfatal) using a combination of case-based (from laboratory-confirmed influenza surveillance) and ecological studies, as well as data from healthcare utilization surveys in South Africa during 2013-2015. In addition, we compared estimates of medically attended influenza-associated respiratory illness, obtained from case-based and ecological studies. Rates were reported per 100 000 individuals in the population. RESULTS: The estimated mean annual number of influenza-associated illness episodes was 10 737 847 (19.8% of 54 096 705 inhabitants). Of these episodes, 10 598 138 (98.7%) were mild, 128 173 (1.2%) were severe, nonfatal, and 11 536 (0.1%) were fatal. There were 2 718 140 (25.6%) mild, 56 226 (43.9%) severe, nonfatal, and 4945 (42.8%) medically attended should be after fatal episodes. Influenza-associated respiratory illness accounted for 99.2% (10 576 146) of any mild, 65.5% (83 941) of any severe, nonfatal, and 33.7% (3893) of any fatal illnesses. Ecological and case-based estimates of medically attended, influenza-associated, respiratory mild (rates: ecological, 1778.8, vs case-based, 1703.3; difference, 4.4%), severe, nonfatal (rates: ecological, 88.6, vs case-based, 75.3; difference, 15.0%), and fatal (rates: ecological, 3.8, vs case-based, 3.5; difference, 8.4%) illnesses were similar. CONCLUSIONS: There was a substantial burden of influenza-associated symptomatic illness, including severe, nonfatal and fatal illnesses, and a large proportion was nonmedically attended. Estimates, including only influenza-associated respiratory illness, substantially underestimated influenza-associated, severe, nonfatal and fatal illnesses. Ecological and case-based estimates were found to be similar for the compared categories.