Risk Factors for Severe COVID-19 Among Children and Adolescents Enrolled in Acute Respiratory Infection Sentinel Surveillance in South Africa, 2020-2022.

BACKGROUND: Identifying children at risk for severe COVID-19 disease from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may guide future mitigation interventions. Using sentinel surveillance data, we aimed to identify risk factors for SARS-CoV-2-associated hospitalisation among patients aged ≤ 18 years with respiratory illness. METHODS: From April 2020 to March 2022, patients meeting study case definitions were enrolled at four outpatient influenza-like illness (ILI) and five inpatient severe respiratory infection (SRI) surveillance sites and tested for SARS-CoV-2 infection using polymerase chain reaction (PCR). Each ILI clinic shared a catchment area with its corresponding SRI hospital. Potential risk factors for SARS-CoV-2-associated hospitalisation were analysed using multivariable logistic regression by comparing inpatient versus outpatient SARS-CoV-2 cases. RESULTS: Of 4688 participants aged ≤ 18 years, 4556 (97%) with complete PCR and HIV data were included in the analysis. Among patients with ILI and SRI, 92/1145 (8%) and 154/3411 (5%) tested SARS-CoV-2 positive, respectively. Compared to outpatients, hospitalised SARS-CoV-2 cases were associated with age < 6 months ([adjusted odds ratio (aOR) 8.0, 95% confidence interval (CI) 2.7-24.0] versus 1-4 years); underlying medical condition other than HIV [aOR 5.8, 95% CI 2.3-14.6]; laboratory-confirmed Omicron BA.1/BA.2 or Delta variant ([aOR 4.9, 95% CI 1.7-14.2] or [aOR 2.8, 95% CI 1.1-7.3] compared to ancestral SARS-CoV-2); and respiratory syncytial virus coinfection [aOR 6.2, 95% CI 1.0-38.5]. CONCLUSION: Aligning with previous research, we identified age < 6 months or having an underlying condition as risk factors for SARS-CoV-2-associated SRI hospitalisation and demonstrated the potential of sentinel surveillance to monitor COVID-19 in children.

Genomic diversity and antimicrobial susceptibility of invasive Neisseria meningitidis in South Africa, 2016-2021.

BACKGROUND: Invasive meningococcal isolates in South Africa have in previous years (<2008) been characterized by serogroup B, C, W and Y lineages over time, with penicillin intermediate resistance (peni) at 6%. We describe the population structure and genomic markers of peni among invasive meningococcal isolates in South Africa, 2016-2021. METHODS: Meningococcal isolates were collected through national, laboratory-based invasive meningococcal disease (IMD) surveillance. Phenotypic antimicrobial susceptibility testing and whole-genome sequencing were performed, and the mechanism of reduced penicillin susceptibility was assessed in silico. RESULTS: Of 585 IMD cases reported during the study period, culture and PCR-based capsular group was determined for 477/585 (82%); and 241/477 (51%) were sequenced. Predominant serogroups included NmB (210/477; 44%), NmW (116/477; 24%), NmY (96/477; 20%) and NmC (48/477; 10%). Predominant clonal complexes (CC) were CC41/44 in NmB (27/113; 24%), CC11 in NmW (46/56; 82%), CC167 in NmY (23/44; 53%), and CC865 in NmC (9/24; 38%). Peni was detected in 16% (42/262) of isolates, and was due to the presence of a penA mosaic, with the majority harboring penA7, penA9 or penA14. CONCLUSION: IMD lineages circulating in South Africa were consistent with those circulating prior to 2008, however peni was higher than previously reported, and occurred in a variety of lineages.

Evaluating the Prevalence and Risk Factors of Schistosomiasis Amongst School-Aged Children in Low- and Middle-Income Communities: Ehlanzeni District Municipality, South Africa, 2015-2021.

This study aimed to assess the prevalence and identify risk factors of schistosomiasis among school-aged children in low- and middle-income communities. A retrospective cross-sectional study was conducted to review patient records of school-age children. Data on gender, age, sub-district, area residing in, patient status, history of bilharzia, presence of blood in the urine, and schistosomiasis diagnoses were collected. The data were analyzed using IBM Statistical Package for the Social Sciences (SPSS) version 27. Logistic regression was employed to determine the factors associated with schistosomiasis. The overall prevalence of schistosomiasis in the study population was 75%, with higher prevalence observed among male children (89%), children aged between 10 and 14 years (59%), urban areas (51%), and rural-dominated districts, particularly Bushbuckridge (42%) and City of Mbombela (51%). Age, especially 10-14 years old (p ˂ 0.01; 95%CI: 1.98-2.29), a history of bilharzia (p = 0.01; 95%CI: 1.15-1.96), and the presence of blood in urine (p ˂ 0.01; 95%CI: 2.02-2.40) were significantly associated with schistosomiasis while being a female child was found to be a protective factor (AOR: 0.35; CI 0.35-0.41). This study underscores the importance of implementing robust screening procedures and the necessity for health education to mitigate the high prevalence of schistosomiasis and prevent its further spread.

Impact of prior cryptococcal antigen screening on in-hospital mortality in cryptococcal meningitis or fungaemia among HIV-seropositive individuals in South Africa: a cross-sectional observational study.

OBJECTIVES: We investigated whether patients with cryptococcal meningitis (CM) or fungaemia detected through South Africa's laboratory cryptococcal antigen (CrAg) screening programme had better outcomes than those presenting directly to the hospital. METHODS: We compared 14-day in-hospital case-fatality ratios of HIV-seropositive individuals with CD4 counts below 100 cells/µL and laboratory-confirmed CM/fungaemia from 2017-2021, with or without evidence of a positive blood CrAg test within 14 days prior to diagnosis. We evaluated whether the impact of prior CrAg screening on mortality varied according to the study period (pre-COVID-19: before March 2020 vs. COVID-19: after March 2020). RESULTS: Overall, 24.5% (830/3390) of patients had a prior positive CrAg test within 14 days of diagnosis. CrAg-screened patients were less likely to have an altered mental status at baseline than non-CrAg-screened patients (38.1% [296/776] vs. 42.6% [1010/2372], p = 0.03), and had a lower crude 14-day case-fatality ratio (24.7% [205/830] vs. 28.3% [724/2560]; OR, 0.83 [95% CI, 0.69-0.99]; p = 0.045). Previous CrAg screening was associated with a greater reduction in the crude 14-day mortality during the COVID-19 period (OR, 0.64 [0.47-0.87]; p = 0.005) compared with before (OR, 0.95 [0.76-1.19]; p = 0.68). After adjustment, previous CrAg screening within 14 days was associated with increased survival only during the COVID-19 period (adjusted OR, 0.70 [0.51-0.96]; p = 0.03). DISCUSSION: Previous CrAg screening was associated with a survival benefit in patients hospitalized with CM/fungaemia during the COVID-19 period, with fewer patients having an altered mental status at baseline, suggesting that these patients may have been diagnosed with cryptococcosis earlier.

Risk Factors for Severe Coronavirus Disease 2019 Among Human Immunodeficiency Virus-Infected and -Uninfected Individuals in South Africa, April 2020-March 2022: Data From Sentinel Surveillance.

Background: Data on risk factors for coronavirus disease 2019 (COVID-19)-associated hospitalization and mortality in high human immunodeficiency virus (HIV) prevalence settings are limited. Methods: Using existing syndromic surveillance programs for influenza-like-illness and severe respiratory illness at sentinel sites in South Africa, we identified factors associated with COVID-19 hospitalization and mortality. Results: From April 2020 through March 2022, severe acute respiratory syndrome coronavirus 2 was detected in 24.0% (660 of 2746) of outpatient and 32.5% (2282 of 7025) of inpatient cases. Factors associated with COVID-19-associated hospitalization included the following: older age (25-44 [adjusted odds ratio {aOR}= 1.8, 95% confidence interval (CI) = 1.1-2.9], 45-64 [aOR = 6.8, 95% CI = 4.2-11.0] and ≥65 years [aOR = 26.6, 95% CI = 14.4-49.1] vs 15-24 years); black race (aOR, 3.3; 95% CI, 2.2-5.0); obesity (aOR, 2.3; 95% CI, 1.4-3.9); asthma (aOR, 3.5; 95% CI, 1.4-8.9); diabetes mellitus (aOR, 5.3; 95% CI, 3.1-9.3); HIV with CD4 ≥200/mm3 (aOR, 1.5; 95% CI, 1.1-2.2) and CD4 <200/mm3 (aOR, 10.5; 95% CI, 5.1-21.6) or tuberculosis (aOR, 12.8; 95% CI, 2.8-58.5). Infection with Beta (aOR, 0.5; 95% CI, .3-.7) vs Delta variant and being fully vaccinated (aOR, 0.1; 95% CI, .1-.3) were less associated with COVID-19 hospitalization. In-hospital mortality was increased in older age (45-64 years [aOR, 2.2; 95% CI, 1.6-3.2] and ≥65 years [aOR, 4.0; 95% CI, 2.8-5.8] vs 25-44 years) and male sex (aOR, 1.3; 95% CI, 1.0-1.6) and was lower in Omicron-infected (aOR, 0.3; 95% CI, .2-.6) vs Delta-infected individuals. Conclusions: Active syndromic surveillance encompassing clinical, laboratory, and genomic data identified setting-specific risk factors associated with COVID-19 severity that will inform prioritization of COVID-19 vaccine distribution. Elderly people with tuberculosis or people with HIV, especially severely immunosuppressed, should be prioritized for vaccination.

Case-fatality and sequelae following acute bacterial meningitis in South Africa, 2016 through 2020.

OBJECTIVES: Providing country-specific estimates of case fatality and sequelae from bacterial meningitis (BM) is important to evaluate and monitor progress toward the World Health Organization's roadmap to "defeating meningitis by 2030". METHODS: From 2016-2020, GERMS-SA conducted enhanced surveillance at 26 hospitals across South Africa. Episodes of laboratory-confirmed BM due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis were included. Risk factors for in-hospital death and sequelae at hospital discharge among survivors were analyzed. RESULTS: Of 12,717 invasive bacterial infections reported nationally, 39% (4980) were from enhanced surveillance sites, including 4159 pneumococcal, 640 H. influenzae, and 181 meningococcal infections. BM accounted for 32% (1319/4159) of pneumococcal, 21% (136/640) of H. influenzae, and 83% (151/181) of meningococcal invasive diseases. Clinical data were available for 91% (1455/1606) of BM: 26% (376/1455) were aged <5 years, 50% (726/1455) were female, and 62% (723/1171) with known HIV results, were HIV-infected. In-hospital case fatality was 37% (534/1455), and 24% (222/921) of survivors had adverse sequelae. Risk factors for death included altered mental status, HIV infection, and comorbidities. Risk factors for adverse sequelae included altered mental status and antimicrobial nonsusceptibility. CONCLUSION: BM in South Africa has a high case fatality, and adverse sequelae frequently occur among survivors. Those with comorbidities (including HIV) are at the highest risk.

Culture-confirmed neonatal bloodstream infections and meningitis in South Africa, 2014-19: a cross-sectional study.

BACKGROUND: Few population-level estimates of invasive neonatal infections have been reported from sub-Saharan Africa. We estimated the national incidence risk, aetiology, and pathogen antimicrobial susceptibility for culture-confirmed neonatal bloodstream infections and meningitis in South Africa. METHODS: We conducted a cross-sectional study of neonates (<28 days of life) admitted to neonatal or paediatric wards of 256 public sector health facilities in South Africa during 2014-19. Diagnostic pathology records from Jan 1, 2014, to Dec 31, 2019, were extracted from a national pathology data warehouse. A case was defined as a neonate with at least one positive blood or cerebrospinal fluid culture during a 14-day period. Incidence risk was calculated using annual numbers of registered livebirths. Among the causative pathogens identified, we calculated the proportion of cases attributed to each of them, as well as the rates of antibiotic susceptibility of Gram-positive and Gram-negative bacteria. FINDINGS: Among 43 438 records of positive cultures, there were 37 631 incident cases of neonatal infection with at least one pathogen isolated. The overall incidence risk of culture-confirmed infections was 6·0 per 1000 livebirths (95% CI 6·0-6·1). The incidence risk of late-onset sepsis (days 3-27 of life) was 4·9 per 1000 livebirths (4·9-5·0) and that of early-onset sepsis (days 0-2 of life) was 1·1 per 1000 livebirths (1·1-1·1); risk ratio 4·4 (95% CI 4·3-4·5). The cause of infection differed by syndrome, timing of infection onset, facility, and province, although Klebsiella pneumoniae (26%), Acinetobacter baumannii (13%), and Staphylococcus aureus (12%) were the dominant pathogens overall. Gram-negative bacteria had declining susceptibility to most antibiotics over the study period. INTERPRETATION: We found a high incidence risk of late-onset sepsis with provincial variations, predominance of K pneumoniae, and declining antibiotic susceptibility among Gram-negative bacteria. This national surveillance in an upper-middle-income country provides a baseline burden of neonatal infections against which the impact of future clinical and public health interventions can be measured. FUNDING: Bill & Melinda Gates Foundation.

Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study.

BACKGROUND: Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. METHODS: In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. FINDINGS: From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38·7%) individuals received a flucytosine-containing regimen and 943 (61·3%) received another regimen. The median age was 36 years (IQR 32-43) and 906 (58·9%) participants were male and 633 (41·1%) were female. The crude in-hospital case-fatality ratio was 23·9% (95% CI 20·0-27·0; 143 of 596) in those treated with flucytosine-containing regimens and 37·2% (95% CI 34·0-40·0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1·95 [95% CI 1·53-2·48]; p<0·0001) and those who were antiretroviral treatment-experienced (aOR 1·30 [1·02-1·67]; p=0·033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0·47 [95% CI 0·35-0·64]; p<0·0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8-15) versus 17 days (13-21) in the comparison group (p=0·0010). INTERPRETATION: In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. FUNDING: National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. TRANSLATION: For the Zulu translation of the abstract see Supplementary Materials section.

Study protocol for a population-based observational surveillance study of culture-confirmed neonatal bloodstream infections and meningitis in South Africa: Baby GERMS-SA.

INTRODUCTION: Worldwide, neonatal mortality remains high accounting for 47% of childhood deaths in 2019 and including an estimated 500 000 deaths from neonatal infections. While 42% of global neonatal deaths occur in sub-Saharan Africa, there is limited understanding of population-level burden and aetiology of neonatal infections outside tertiary-level institutions. METHODS AND ANALYSIS: We aim to implement the first population-level surveillance for bloodstream infections and meningitis among neonates aged <28 days in South Africa. Tier 1 will include national surveillance of culture-confirmed neonatal infections at all public-sector hospitals describing infection incidence risk, pathogen profile and antimicrobial susceptibility by institution, province and healthcare level (2014-2021). Tier 2 (nested within tier 1) will be conducted at six regional neonatal units over 12 months, will compare the clinical characteristics of neonates with early-onset and late-onset infections and identify potentially modifiable risk factors for mortality. Through tier 2, we will determine the antimicrobial susceptibility of neonatal pathogens, evaluate the appropriateness of empiric antibiotic prescribing and determine the genomic epidemiology of multidrug resistant bacterial and fungal pathogens. ETHICS AND DISSEMINATION: Ethics clearance was obtained from the Human Research Ethics Committee of the University of the Witwatersrand (M190320). Funding for the study was obtained through a grant from the Bill and Melinda Gates Foundation (OPP1208882). Baby GERMS-SA aims to impact on national policy, resource allocation and neonatal guidelines by describing the national burden of neonatal infections in South Africa. In addition, end-users in neonatal units will benefit from a facility-level dashboard displaying key indicators of the surveillance findings.

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.

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.

Human Immunodeficiency Virus Infection Is Associated With Increased Meningococcal Carriage Acquisition Among First-year Students in 2 South African Universities.

BACKGROUND: Invasive meningococcal disease clusters occur among university students and may reflect higher carriage prevalence among this population. We aimed to measure meningococcal carriage prevalence, acquisition, and risk factors among first-year university students in South Africa. METHODS: In summer-autumn 2017, after consenting to participate, we collected oropharyngeal swabs and questionnaires on carriage risk factors and tested students for HIV at 2 universities, during registration week (survey 1) and 6-8 weeks later (survey 2). Meningococci were detected by culture and polymerase chain reaction. RESULTS: We enrolled 2120 students at registration. Mean age was 18.5 years, 59% (1252/2120) were female and 0.8% (16/1984) had HIV. Seventy-eight percent of students returned for survey 2 (1655/2120). Among the cohort, carriage prevalence was 4.7% (77/1655) at registration, increasing to 7.9% (130/1655) at survey 2: 5.0% (83) acquired new carriage, 2.8% (47) had persistent carriage, 1.8% (30) cleared the initial carriage, and 90.3% (1495) remained carriage free. At both surveys, nongenogroupable meningococci predominated, followed by genogroups Y, B, W, and C. On multinomial analysis, risk factors for carriage acquisition included attending nightclubs (adjusted relative risk ratio [aRRR], 2.1; 95% CI, 1.1-4.0), having intimate kissing partners (aRRR, 1.8; 95% CI, 1.1-2.9) and HIV (aRRR, 5.0; 95% CI, 1.1-24.4). CONCLUSIONS: Meningococcal carriage among first-year university students increased after 2 months. Sociobehavioral risk factors were associated with increased carriage for all analyses. HIV was associated with carriage acquisition. Until vaccination programs become mandatory in South African universities, data suggest that students with HIV could benefit most from meningococcal vaccination.

Pathways to care and outcomes among hospitalised HIV-seropositive persons with cryptococcal meningitis in South Africa.

INTRODUCTION: Cryptococcus causes 15% of AIDS-related deaths and in South Africa, with its high HIV burden, is the dominant cause of adult meningitis. Cryptococcal meningitis (CM) mortality is high, partly because patients enter care with advanced HIV disease and because of failure of integrated care following CM diagnosis. We evaluated pathways to hospital care, missed opportunities for HIV testing and initiation of care. METHODS: We performed a cross-sectional study at five public-sector urban hospitals. We enrolled adults admitted with a first or recurrent episode of cryptococcal meningitis. Study nurses conducted interviews, supplemented by a prospective review of medical charts and laboratory records. RESULTS: From May to October 2015, 102 participants were enrolled; median age was 40 years (interquartile range [IQR] 33.9-46.7) and 56 (55%) were male. In the six weeks prior to admission, 2/102 participants were asymptomatic, 72/100 participants sought care at a public-sector facility, 16/100 paid for private health care. The median time from seeking care to admission was 4 days (IQR, 0-27 days). Of 94 HIV-seropositive participants, only 62 (66%) knew their status and 41/62 (66%) had ever taken antiretroviral treatment. Among 13 participants with a known previous CM episode, none were taking fluconazole maintenance therapy. In-hospital management was mostly amphotericin B; in-hospital mortality was high (28/92, 30%). Sixty-four participants were discharged, 92% (59/64) on maintenance fluconazole, 4% (3/64) not on fluconazole and 3% (2/64) unknown. Twelve weeks post-discharge, 31/64 (48%) participants were lost to follow up. By 12 weeks post discharge 7/33 (21%) had died. Interviewed patients were asked if they were still on fluconazole, 11% (2/18) were not. CONCLUSIONS: Among hospitalised participants with CM, there were many missed opportunities for HIV care and linkage to ART prior to admission. Universal reflex CrAg screening may prompt earlier diagnosis of cryptococcal meningitis but there is a wider problem of timely linkage to care for HIV-seropositive people.

Can pneumococcal meningitis surveillance be used to assess the impact of pneumococcal conjugate vaccine on total invasive pneumococcal disease? A case-study from South Africa, 2005-2016.

INTRODUCTION: South Africa introduced seven-valent pneumococcal conjugate vaccine (PCV7) in 2009 and PCV13 in 2011. We aimed to compare the estimated impact of PCV on pneumococcal meningitis (PM) to impact of PCV on total invasive pneumococcal disease (tIPD) based on risk reduction after PCV introduction. METHODS: We conducted national, laboratory-based surveillance for tIPD during 2005-2016. We estimated and compared rates of PCV13 and non-PCV13 serotype disease among tIPD and PM in individuals aged <5 years and ≥5 years, and compared these rates between the 2005-2008 pre-PCV introduction period and two time points after PCV introduction, 2012 and 2016. RESULTS: We enrolled 45,853 tIPD cases; 17,251 (38%) were PM. By 2016, IPD caused by all serotypes decreased 55% (95%CI -57% to -53%) for tIPD, and 54% for PM (95%CI -58% to -51%), 0.7% difference between estimates (p = 0.7). No significant differences were observed between PCV7-serotype disease reduction in tIPD and PM in both age groups or the additional 6 serotypes included in PCV13 in <5 year olds in 2012 and 2016. In 2012 there was a significant difference between increases in non-PCV13 serotype disease in those ≥5 years for tIPD and PM (32% greater increase in PM, p < 0.001), but this difference was absent by 2016. There was a significant difference between the estimated decrease in additional PCV13 type disease in 2016 between tIPD and PM for those aged ≥5 years (28% greater reduction in PM, p = 0.008). CONCLUSION: PM showed similar reductions to tIPD seven years after PCV introduction in vaccine serotype disease in those <5 years, and increases in non-vaccine serotype disease in all ages.

Invasive Pneumococcal Disease in Neonates Prior to Pneumococcal Conjugate Vaccine Use in South Africa: 2003-2008.

BACKGROUND: Neonatal invasive pneumococcal disease (IPD) in developing countries is poorly described. We provide a baseline description of neonatal IPD in South Africa, before implementation of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2009. METHODS: Data from children (age ≤ 2 years) with IPD (pneumococcus identified from a normally sterile specimen) from January 2003 to December 2008 were extracted from a national laboratory-based surveillance database. Clinical and laboratory characteristics of IPD among neonates (0-27 days old) was compared with IPD among young children (≥ 28 days ≤ 2 years). Early-onset IPD (0-6 days old) was compared with late-onset IPD (≥ 7-27 days old). Isolates were serotyped using the Quellung reaction. RESULTS: Overall 27,630 IPD cases were reported. Of the 26,277 (95%) with known ages, 6583 (25%) were ≤ 2 years of age, of which 4.5% (294/6583) were neonates. The estimated annual incidence of neonatal IPD in 2008 was 5 per 100,000 live births. Fifty-one percent of neonates with IPD presented with early-onset IPD. Case fatality ratios (CFRs) were high in both groups, 31% (28/89) in neonatal IPD versus 26% (614/2383) in non-neonatal IPD (P = 0.18). Among neonates, the meningitis cases (15/37, 41%) were associated with the highest CFR. The 13-valent pneumococcal conjugate vaccine (PCV13) serotypes accounted for 69% (134/194) of neonatal IPD isolates. CONCLUSIONS: Pneumococcal neonatal disease in South Africa was not uncommon before PCV introduction and is associated with a high CFR. The indirect effect on neonatal IPD of PCV rollout requires further evaluation.

Risk factors for bacterial zoonotic pathogens in acutely febrile patients in Mpumalanga Province, South Africa.

Endemic zoonoses, such as Q fever and spotted fever group (SFG) rickettsiosis, are prevalent in South Africa, yet often undiagnosed. In this study, we reviewed the demographics and animal exposure history of patients presenting with acute febrile illness to community health clinics in Mpumalanga Province to identify trends and risk factors associated with exposure to Coxiella burnetii, the causative agent of Q fever, and infection by SFG Rickettsia spp. Clinical and serological data and questionnaires elucidating exposure to animals and their products were obtained from 141 acutely febrile patients between 2012 and 2016. Exposure or infection status to C. burnetii and SFG Rickettsia spp. was determined by presence of IgG or IgM antibodies. Logistic regression models were built for risk factor analysis. Clinical presentation of patients infected by SFG rickettsiosis was described. There were 37/139 (27%) patients with a positive C. burnetii serology, indicative of Q fever exposure. Patients who had reported attending cattle inspection facilities ("dip tanks") were 9.39 times more likely to be exposed to Q fever (95% CI: 2.9-30.4). Exposure risk also increased with age (OR: 1.03, 95% CI: 1.002-1.06). Twenty-one per cent of febrile patients (24/118) had evidence of acute infection by SFG Rickettsia spp. Similarly, attending cattle inspection facilities was the most significant risk factor (OR: 8.48, 95% CI: 1.58-45.60). Seropositivity of females showed a significant OR of 8.0 when compared to males (95% CI: 1.49-43.0), and consumption of livestock was associated with a decreased risk (OR: 0.02, 95% CI: 0.001-0.54). A trend between domestic cat contact and SFG rickettsiosis was also noted, albeit borderline non-significant. In this endemic region of South Africa, an understanding of risk factors for zoonotic pathogens, including exposure to domestic animals, can help clinic staff with diagnosis and appropriate therapeutic management of acutely febrile patients as well as identify target areas for education and prevention strategies.

Declining Incidence of Invasive Meningococcal Disease in South Africa: 2003-2016.

BACKGROUND: Invasive meningococcal disease (IMD) is endemic to South Africa, where vaccine use is negligible. We describe the epidemiology of IMD in South Africa. METHODS: IMD cases were identified through a national, laboratory-based surveillance program, GERMS-SA, from 2003-2016. Clinical data on outcomes and human immunodeficiency virus (HIV) statuses were available from 26 sentinel hospital sites. We conducted space-time analyses to detect clusters of serogroup-specific IMD cases. RESULTS: Over 14 years, 5249 IMD cases were identified. The incidence was 0.97 cases per 100 000 persons in 2003, peaked at 1.4 cases per 100 000 persons in 2006, and declined to 0.23 cases per 100 000 persons in 2016. Serogroups were confirmed in 3917 (75%) cases: serogroup A was present in 4.7% of cases, B in 23.3%, C in 9.4%; W in 49.5%; Y in 12.3%, X in 0.3%; Z in 0.1% and 0.4% of cases were non-groupable. We identified 8 serogroup-specific, geo-temporal clusters of disease. Isolate susceptibility was 100% to ceftriaxone, 95% to penicillin, and 99.9% to ciprofloxacin. The in-hospital case-fatality rate was 17% (247/1479). Of those tested, 36% (337/947) of IMD cases were HIV-coinfected. The IMD incidence in HIV-infected persons was higher for all age categories, with an age-adjusted relative risk ratio (aRRR) of 2.5 (95% confidence interval [CI] 2.2-2.8; P < .001) from 2012-2016. No patients reported previous meningococcal vaccine exposure. Patients with serogroup W were 3 times more likely to present with severe disease than those with serogroup B (aRRR 2.7, 95% CI 1.1-6.3); HIV coinfection was twice as common with W and Y diseases (aRRR W = 1.8, 95% CI 1.1-2.9; aRRR Y = 1.9, 95% CI 1.0-3.4). CONCLUSIONS: In the absence of significant vaccine use, IMD in South Africa decreased by 76% from 2003-2016. HIV was associated with an increased risk of IMD, especially for serogroup W and Y diseases.

Prevalence of Selected Zoonotic Diseases and Risk Factors at a Human-Wildlife-Livestock Interface in Mpumalanga Province, South Africa.

A lack of surveillance and diagnostics for zoonotic diseases in rural human clinics limits clinical awareness of these diseases. We assessed the prevalence of nine zoonotic pathogens in a pastoral, low-income, HIV-endemic community bordering wildlife reserves in South Africa. Two groups of participants were included: malaria-negative acute febrile illness (AFI) patients, called febrilers, at three clinics (n = 74) and second, farmers, herders, and veterinary staff found at five government cattle dip-tanks, called dip-tanksters (n = 64). Blood samples were tested using one PCR (Bartonella spp.) and eight antibody-ELISAs, and questionnaires were conducted to assess risk factors. Seventy-seven percent of febrilers and 98% of dip-tanksters had at least one positive test. Bartonella spp. (PCR 9.5%), spotted fever group (SFG) Rickettsia spp. (IgM 24.1%), Coxiella burnetii. (IgM 2.3%), and Leptospira spp. (IgM 6.8%) were present in febrilers and could have been the cause of their fever. Dip-tanksters and febrilers had evidence of past infection to Rickettsia spp. (IgG 92.2% and 63.4%, respectively) and C. burnetii (IgG 60.9% and 37.8%, respectively). No Brucella infection or current Bartonella infection was found in the dip-tanksters, although they had higher levels of recent exposure to Leptospira spp. (IgM 21.9%) compared to the febrilers. Low levels of West Nile and Sindbis, and no Rift Valley fever virus exposure were found in either groups. The only risk factor found to be significant was attending dip-tanks in febrilers for Q fever (p = 0.007). Amoxicillin is the local standard treatment for AFI, but would not be effective for Bartonella spp. infections, SFG rickettsiosis, Q fever infections, or the viral infections. There is a need to revise AFI treatment algorithms, educate medical and veterinary staff about these pathogens, especially SFG rickettsiosis and Q fever, support disease surveillance systems, and inform the population about reducing tick and surface water contact.

Estimated severe pneumococcal disease cases and deaths before and after pneumococcal conjugate vaccine introduction in children younger than 5 years of age in South Africa.

INTRODUCTION: Streptococcus pneumoniae is a leading cause of severe bacterial infections globally. A full understanding of the impact of pneumococcal conjugate vaccine (PCV) on pneumococcal disease burden, following its introduction in 2009 in South Africa, can support national policy on PCV use and assist with policy decisions elsewhere. METHODS: We developed a model to estimate the national burden of severe pneumococcal disease, i.e. disease requiring hospitalisation, pre- (2005-2008) and post-PCV introduction (2012-2013) in children aged 0-59 months in South Africa. We estimated case numbers for invasive pneumococcal disease using data from the national laboratory-based surveillance, adjusted for specimen-taking practices. We estimated non-bacteraemic pneumococcal pneumonia case numbers using vaccine probe study data. To estimate pneumococcal deaths, we applied observed case fatality ratios to estimated case numbers. Estimates were stratified by HIV status to account for the impact of PCV and HIV-related interventions. We assessed how different assumptions affected estimates using a sensitivity analysis. Bootstrapping created confidence intervals. RESULTS: In the pre-vaccine era, a total of approximately 107,600 (95% confidence interval [CI] 83,000-140,000) cases of severe hospitalised pneumococcal disease were estimated to have occurred annually. Following PCV introduction and the improvement in HIV interventions, 41,800 (95% CI 28,000-50,000) severe pneumococcal disease cases were estimated in 2012-2013, a rate reduction of 1,277 cases per 100,000 child-years. Approximately 5000 (95% CI 3000-6000) pneumococcal-related annual deaths were estimated in the pre-vaccine period and 1,900 (95% CI 1000-2500) in 2012-2013, a mortality rate difference of 61 per 100,000 child-years. CONCLUSIONS: While a large number of hospitalisations and deaths due to pneumococcal disease still occur among children 0-59 months in South Africa, we found a large reduction in this estimate that is temporally associated with PCV introduction. In HIV-infected individuals the scale-up of other interventions, such as improvements in HIV care, may have also contributed to the declines in pneumococcal burden.

Effectiveness of the 13-valent pneumococcal conjugate vaccine against invasive pneumococcal disease in South African children: a case-control study.

BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) was designed to include disease-causing serotypes that are important in low-income and middle-income countries. Vaccine effectiveness estimates are scarce in these settings. South Africa replaced PCV7 with PCV13 in 2011 using a 2 + 1 schedule. We aimed to assess the effectiveness of two or more doses of PCV13 against invasive pneumococcal disease in children with HIV infection and in those not infected with HIV. METHODS: Cases of invasive pneumococcal disease in children aged 5 years or younger were identified through national laboratory-based surveillance. Isolates were serotyped with the Quellung reaction or PCR. We sought in-hospital controls for every case, matched for age, HIV status, and study site. We aimed to enrol four controls for every case not infected with HIV and six controls for every case with HIV infection (case-control sets). With conditional logistic regression, we calculated vaccine effectiveness as a percentage, with the equation 1 - [adjusted odds ratio for vaccination] × 100. We included data from an earlier investigation of PCV7 to assess vaccine effectiveness in children exposed to but not infected with HIV and in malnourished children not infected with HIV. FINDINGS: Between January, 2012, and December, 2014, we enrolled children aged 16 weeks or older to our study: 240 were cases not infected with HIV, 75 were cases with HIV infection, 1118 were controls not infected with HIV, and 283 were controls with HIV infection. The effectiveness of two or more doses of PCV13 against PCV13-serotype invasive pneumococcal disease was 85% (95% CI 37 to 96) among 11 case-control sets of children not infected with HIV and 91% (-35 to 100) among three case-control sets of children with HIV infection. PCV13 effectiveness among 26 case-control sets of children not infected with HIV was 52% (95% CI -12 to 79) against all-serotype invasive pneumococcal disease and 94% (44 to 100) for serotype 19A. Vaccine effectiveness against PCV7-serotype invasive pneumococcal disease was 87% (95% CI 38 to 97) in children exposed to HIV but uninfected and 90% (53 to 98) in malnourished children not infected with HIV. INTERPRETATION: Our results indicate that PCV13 in a 2 + 1 schedule is effective for preventing vaccine-type pneumococcal infections in young children not infected with HIV, including those who are malnourished or who have been exposed to HIV. Although the point estimate for PCV13 vaccine effectiveness in children infected with HIV was high, it did not reach significance, possibly because of the small sample size. These findings support recommendations for widespread use of pneumococcal conjugate vaccine in low-income and middle-income countries. FUNDING: Gavi, The Vaccine Alliance.