Susan Meiring

Effects of Vaccination on Invasive Pneumococcal Disease in South Africa

BACKGROUND In South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease. METHODS We conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups. RESULTS Surveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (-89%; 95% confidence interval [CI], -92 to -86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, -89 to -79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, -63 to -50), from 3.7 to 1.6 cases per 100,000 person-years. CONCLUSIONS Rates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.).

Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa.

Objectives:We aimed to compare the incidence of meningococcal disease amongst HIV-infected and uninfected individuals and to evaluate whether HIV is a risk factor for mortality and bacteremia amongst patients with meningococcal disease. Design:Cohort surveillance study. Methods:We conducted laboratory-based surveillance for meningococcal disease in Gauteng Province, South Africa. HIV status and outcome data were obtained at sentinel sites. Incidence in HIV-infected and uninfected persons was calculated assuming a similar age-specific HIV prevalence in tested and untested individuals. Risk factors for death and bacteremia (as compared with meningitis) were evaluated using multivariable logistic regression. Results:From 2003 to 2007, 1336 meningococcal cases were reported. Of 504 patients at sentinel sites with known outcome, 308 (61%) had HIV serostatus data. HIV prevalence amongst cases of meningococcal disease was higher than the population HIV prevalence in all age groups. The incidence of meningococcal disease in HIV-infected individuals was elevated in all age groups with an age-adjusted relative risk of 11.3 [95% confidence interval (CI) 8.9–14.3, P < 0.001]. The case-fatality ratio (CFR) was 20% (27/138) amongst HIV-infected and 11% (18/170) amongst HIV-uninfected individuals [odds ratio (OR) 2.1, 95% CI 1.1–3.9]. On multivariable analysis, CFR was greater amongst patients with bacteremia (35%, 29/82) compared with meningitis (7%, 16/226) (OR 7.8, 95% CI 3.4–17.7). HIV infection was associated with increased odds of bacteremia (OR 2.7, 95% CI 1.5–5.0). Conclusion:HIV-infected individuals may be at increased risk of meningococcal disease. The increased CFR in HIV-infected patients may be explained by their increased odds of bacteremia compared to meningitis.

Emergence of levofloxacin-non-susceptible Streptococcus pneumoniae and treatment for multidrug-resistant tuberculosis in children in South Africa: a cohort observational surveillance study

BACKGROUND Use of fluoroquinolones to treat paediatric cases of multidrug-resistant tuberculosis could affect the emergence of resistance to this class of drugs. Our aim was to estimate the incidence of, and risk factors for, invasive pneumococcal disease caused by fluoroquinolone-resistant Streptococcus pneumoniae in children in South Africa. METHODS 21,521 cases of invasive pneumococcal disease were identified by active national surveillance between 2000 and 2006, with enhanced surveillance at 15 sentinel hospitals in seven provinces introduced in 2003. We screened 19,404 isolates (90% of cases) for ofloxacin resistance and measured levofloxacin minimum inhibitory concentrations (MICs) for all isolates that were ofloxacin resistant. Non-susceptibility to levofloxacin was defined as an MIC of 4 mg/L or more. Nasopharyngeal pneumococcal carriage was assessed in 65 children in two tuberculosis hospitals where invasive pneumococcal disease caused by levofloxacin-non-susceptible S pneumoniae had been detected. FINDINGS 12 cases of invasive pneumococcal disease were identified as being non-susceptible to levofloxacin, all in children aged under 15 years. All isolates were rifampicin resistant. Outcome was known for 11 of these patients; five (45%) died. Invasive disease caused by levofloxacin-non-susceptible S pneumoniae was associated with a history of tuberculosis treatment (eight [89%] of nine children with non-susceptible isolates had a history of treatment vs 396 [18%] of 2202 children with susceptible isolates; relative risk [RR] 35.78, 95% CI 4.49-285.30) and nosocomial invasive pneumococcal disease (eight [80%] of ten children with non-susceptible isolates had acquired infection nosocomially vs 109 [4%] of 2709 with susceptible isolates; RR 88.96, 19.10-414.29). 31 (89%) of 35 pneumococcal carriers had bacteria that were non-susceptible to levofloxacin. INTERPRETATION Our data suggest that the use of fluoroquinolones to treat multidrug-resistant tuberculosis in children has led to the emergence of invasive pneumococcal disease caused by levofloxacin-non-susceptible S pneumoniae and its nosocomial spread.

Increased Risk for and Mortality From Invasive Pneumococcal Disease in HIV-Exposed but Uninfected Infants Aged <1 Year in South Africa, 2009–2013

BACKGROUND High antenatal human immunodeficiency virus (HIV) seroprevalence rates (∼ 30%) with low perinatal HIV transmission rates (2.5%), due to HIV prevention of mother-to-child transmission program improvements in South Africa, has resulted in increasing numbers of HIV-exposed but uninfected (HEU) children. We aimed to describe the epidemiology of invasive pneumococcal disease (IPD) in HEU infants. METHODS We conducted a cross-sectional study of infants aged <1 year with IPD enrolled in a national, laboratory-based surveillance program for incidence estimations. Incidence was reported for 2 time points, 2009 and 2013. At enhanced sites we collected additional data including HIV status and in-hospital outcome. RESULTS We identified 2099 IPD cases in infants from 2009 to 2013 from all sites. In infants from enhanced sites (n = 1015), 92% had known HIV exposure status and 86% had known outcomes. IPD incidence was highest in HIV-infected infants, ranging from 272 to 654 per 100,000 population between time points (2013 and 2009), followed by HEU (33-88 per 100,000) and HIV-unexposed and uninfected (HUU) infants (18-28 per 100,000). The case-fatality rate in HEU infants (29% [74/253]) was intermediate between HUU (25% [94/377]) and HIV-infected infants (34% [81/242]). When restricted to infants <6 months of age, HEU infants (37% [59/175]) were at significantly higher risk of dying than HUU infants (32% [51/228]; adjusted relative risk ratio, 1.76 [95% confidence interval, 1.09-2.85]). DISCUSSION HEU infants are at increased risk of IPD and mortality from IPD compared with HUU children, especially as young infants. HEU infants, whose numbers will likely continue to increase, should be prioritized for interventions such as pneumococcal vaccination along with HIV-infected infants and children.

Epidemiology of invasive pneumococcal disease in the pre-conjugate vaccine era: South Africa, 2003–2008

INTRODUCTION Dynamics of pneumococcal disease incidence and serotype distribution prior to introduction of pneumococcal conjugate vaccines (PCV) will assist in understanding effects of the vaccine over time and will be important in choosing the optimal PCV formulation. METHODS We conducted active, laboratory-based, national surveillance for invasive pneumococcal disease (IPD) through the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) from 2003 through 2008. Over 130 laboratories report to this system. Pneumococci were serotyped using Quellung and isolates screened for resistance by disk diffusion; minimum inhibitory concentrations were determined on potentially resistant isolates. We used univariate and multivariable multinomial regression models to assess differences between serotypes. RESULTS GERMS-SA identified 8674 cases among children <5 years. Overall, 58% (3849/6668), 65% (4314/6668), and 85% (5669/6668) of cases and 61% (455/751), 64% (482/751), 82% (616/751) of deaths were due to serotypes included in 7-valent PCV, 10-valent PCV and 13-valent PCV, respectively. Serotypes 6A and 19A accounted for 16% (527/3252) of penicillin non-susceptible disease. In 2008, reported incidence of IPD was 6-fold higher in children <1 compared to children 1-4 years of age: 87 per 100,000 population and 14/100,000, respectively. The relative risk of IPD was 21-fold (95% CI, 19-24) and 34-fold (29-41) greater in HIV-infected compared to HIV-uninfected children in the <1 year and 1-4-year-old age groups respectively. On multivariable analysis serotypes 6B (relative risk ratio (RRR) 0.7; confidence interval (CI) 0.5-0.9), 18C (RRR 0.3; CI 0.1-0.5), 1 (RRR 0.2; CI 0.1-0.4) and 8 (RRR 0.2; CI 0.1-0.4) were significantly less common in HIV-infected individuals than serotype 14. CONCLUSIONS All vaccine formulations have the potential to prevent most cases and deaths from IPD in children in South Africa. Vaccines with protection against 19A would be advantageous in South Africa.

A comparison of cases of paediatric-onset and adult-onset cryptococcosis detected through population-based surveillance, 2005-2007.

Objective:We compared the epidemiology of laboratory-confirmed paediatric cryptococcal disease with adult-onset disease in the South African population. Methods:The study was an active, prospective, population-based, laboratory-based surveillance in South Africa. We compared cases of paediatric cryptococcosis (<15 years) with cases of adult-onset cryptococcosis that were reported to the surveillance programme between 1 January 2005 and 31 December 2007. The case definition was based on a positive India ink test, cryptococcal antigen test or cryptococcal culture. Clinical case data were obtained at enhanced surveillance sites. Results:Of 16 192 incident episodes of cryptococcosis in South Africa, 361 (2%) episodes occurred among children. In 2007, incidence was one and 19 cases per 100 000 persons in the general paediatric and adult populations and was 47 and 120 cases per 100 000 persons for HIV-infected children and adults, respectively. Among children, a bimodal peak in incidence was evident in the less than 1-year age group and in the 5 age group. Most children (64%) and adults (63%) were severely immunocompromised (CD4+ T-lymphocyte cell count < 50 cells/&mgr;l) at the time of diagnosis. On multivariable analysis, children were significantly more likely than adults to be male, diagnosed on blood culture, infected with Cryptococcus gattii, treated with amphotericin B and admitted for a longer stay in hospital. Conclusion:This series of 361 cases of paediatric cryptococcosis is by far the largest described to date. The diagnosis of cryptococcosis should be considered in the paediatric HIV-infected population, especially among those who are severely immunocompromised.

Increased risk and mortality of invasive pneumococcal disease in HIV-exposed-uninfected infants <1 year of age in South Africa, 2009-2013

BACKGROUND High antenatal human immunodeficiency virus (HIV) seroprevalence rates (∼ 30%) with low perinatal HIV transmission rates (2.5%), due to HIV prevention of mother-to-child transmission program improvements in South Africa, has resulted in increasing numbers of HIV-exposed but uninfected (HEU) children. We aimed to describe the epidemiology of invasive pneumococcal disease (IPD) in HEU infants. METHODS We conducted a cross-sectional study of infants aged <1 year with IPD enrolled in a national, laboratory-based surveillance program for incidence estimations. Incidence was reported for 2 time points, 2009 and 2013. At enhanced sites we collected additional data including HIV status and in-hospital outcome. RESULTS We identified 2099 IPD cases in infants from 2009 to 2013 from all sites. In infants from enhanced sites (n = 1015), 92% had known HIV exposure status and 86% had known outcomes. IPD incidence was highest in HIV-infected infants, ranging from 272 to 654 per 100,000 population between time points (2013 and 2009), followed by HEU (33-88 per 100,000) and HIV-unexposed and uninfected (HUU) infants (18-28 per 100,000). The case-fatality rate in HEU infants (29% [74/253]) was intermediate between HUU (25% [94/377]) and HIV-infected infants (34% [81/242]). When restricted to infants <6 months of age, HEU infants (37% [59/175]) were at significantly higher risk of dying than HUU infants (32% [51/228]; adjusted relative risk ratio, 1.76 [95% confidence interval, 1.09-2.85]). DISCUSSION HEU infants are at increased risk of IPD and mortality from IPD compared with HUU children, especially as young infants. HEU infants, whose numbers will likely continue to increase, should be prioritized for interventions such as pneumococcal vaccination along with HIV-infected infants and children.

Systemic Shigellosis in South Africa

BACKGROUND Systemic disease due to shigellae is associated with human immunodeficiency virus (HIV), malnutrition, and other immunosuppressed states. We examined the clinical and microbiologic characteristics of systemic shigellosis in South Africa, where rates of HIV infection are high. METHODS From 2003 to 2009, 429 cases of invasive shigellosis were identified through national laboratory-based surveillance. At selected sites, additional information was captured on HIV serostatus and outcome. Isolates were serotyped and antimicrobial susceptibility testing performed. RESULTS Most cases of systemic shigellosis were diagnosed on blood culture (408 of 429 cases; 95%). HIV prevalence was 67% (80 of 120 cases), highest in patients aged 5-54 years, and higher among females (55 of 70 cases; 79%) compared with males (25 of 48 cases; 52%; P = .002). HIV-infected people were 4.1 times more likely to die than HIV-uninfected cases (case-fatality ratio, 29 of 78 HIV-infected people [37%] vs 5 of 40 HIV-uninfected people [13%]; P = .008; 95% confidence interval [CI], 1.5-11.8). The commonest serotype was Shigella flexneri 2a (89 of 292 serotypes [30.5%]). Pentavalent resistance occurred in 120 of 292 isolates (41.1%). There was no difference in multidrug resistance between HIV-infected patients (33 of 71 [46%]) and uninfected patients (12 of 33 [36%]; 95% CI, .65--3.55). CONCLUSIONS Systemic shigellosis is associated with HIV-infected patients, primarily in older girls and women, potentially due to the burden of caring for sick children in the home; interventions need to be targeted here. Death rates are higher in HIV-infected versus uninfected individuals.

Effectiveness of 7-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in HIV-Infected and -Uninfected Children in South Africa: A Matched Case-Control Study

A 2 + 1 seven-valent pneumococcal conjugate vaccine schedule is effective against vaccine-serotype invasive pneumococcal disease (IPD) in HIV-uninfected children and HIV-exposed but -uninfected children and against all-serotype multidrug-resistant IPD in HIV-uninfected children.

Analyses of Pediatric Isolates of Cryptococcus neoformans from South Africa

ABSTRACT Compared to the incidence in adults, cryptococcosis is inexplicably rare among children, even in sub-Saharan Africa, which has the highest prevalence of coinfection with HIV and Cryptococcus neoformans. To explore any mycological basis for this age-related difference in the incidence of cryptococcosis, we investigated isolates of C. neoformans recovered from pediatric and adult patients during a 2-year period in South Africa. From reports to the Group for Enteric, Respiratory, and Meningeal Disease Surveillance in South Africa (GERMS-SA), we reviewed all cases of cryptococcosis in 2005 and 2006. We analyzed one isolate of C. neoformans from each of 82 pediatric patients (<15 years of age) and determined the multilocus sequence type (ST), mating type, ploidy, and allelic profile. This sample included isolates of all three molecular types of serotype A or C. neoformans var. grubii (molecular types VNI, VNII, and VNB) and one AD hybrid. Seventy-seven (94%) of the strains possessed the MATα mating type allele, and five were MAT a. Seventy-five (91%) were haploid, and seven were diploid. A total of 24 different STs were identified. The ratios of each mating type and the proportion of haploids were comparable to those for the isolates that were obtained from 86 adult patients during the same period. Notably, the most prevalent pediatric ST was significantly associated with male patients. Overall, these pediatric isolates exhibited high genotypic diversity. They included a relatively large percentage of diploids and the rarely reported MAT a mating type.