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1.  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 
Cohen, Cheryl | von Mollendorf, Claire | de Gouveia, Linda | Naidoo, Nireshni | Meiring, Susan | Quan, Vanessa | Nokeri, Vusi | Fortuin-de Smit, Melony | Malope-Kgokong, Babatyi | Moore, David | Reubenson, Gary | Moshe, Mamokgethi | Madhi, Shabir A. | Eley, Brian | Hallbauer, Ute | Kularatne, Ranmini | Conklin, Laura | O'Brien, Katherine L. | Zell, Elizabeth R. | Klugman, Keith | Whitney, Cynthia G. | von Gottberg, Anne | Moore, David | Verwey, Charl | Varughese, Sheeba | Archary, Moherndran | Naby, Fathima | Dawood, Khathija | Naidoo, Ramola | Elliott, Gene | Hallbauer, Ute | Eley, Brian | Nuttall, James | Cooke, Louise | Finlayson, Heather | Rabie, Helena | Whitelaw, Andrew | Perez, Dania | Jooste, Pieter | Naidoo, Dhamiran | Kularatne, Ranmini | Reubenson, Gary | Cohen, Cheryl | de Gouveia, Linda | du Plessis, Mignon | Govender, Nevashan | Meiring, Susan | Quan, Vanessa | von Mollendorf, Claire | Fortuin-de Smidt, Melony | Naidoo, Nireshni | Malope-Kgokong, Babatyi | Nokeri, Vusi | Ncha, Relebohile | Lindani, Sonwabo | von Gottberg, Anne | Spies, Barry | Sono, Lino | Maredi, Phasweni | Hamese, Ken | Moshe, Mamokgethi | Nchabeleng, Maphosane | Ngcobo, Ntombenhle | van den Heever, Johann | Madhi, Shabir | Conklin, Laura | Verani, Jennifer | Whitney, Cynthia | Zell, Elizabeth | Loo, Jennifer | Nelson, George | Klugman, Keith | O'Brien, Katherine
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.
Background. South Africa introduced 7-valent pneumococcal conjugate vaccine (PCV7) in April 2009 using a 2 + 1 schedule (6 and 14 weeks and 9 months). We estimated the effectiveness of ≥2 PCV7 doses against invasive pneumococcal disease (IPD) in human immunodeficiency virus (HIV)–infected and -uninfected children.
Methods. IPD (pneumococcus identified from a normally sterile site) cases were identified through national laboratory-based surveillance. Specimens were serotyped by Quellung or polymerase chain reaction. Four controls, matched for age, HIV status, and hospital were sought for each case. Using conditional logistic regression, we calculated vaccine effectiveness (VE) as 1 minus the adjusted odds ratio for vaccination.
Results. From March 2010 through November 2012, we enrolled 187 HIV-uninfected (48 [26%] vaccine serotype) and 109 HIV-infected (43 [39%] vaccine serotype) cases and 752 HIV-uninfected and 347 HIV-infected controls aged ≥16 weeks. Effectiveness of ≥2 PCV7 doses against vaccine-serotype IPD was 74% (95% confidence interval [CI], 25%–91%) among HIV-uninfected and −12% (95% CI, −449% to 77%) among HIV-infected children. Effectiveness of ≥3 doses against vaccine-serotype IPD was 90% (95% CI, 14%–99%) among HIV-uninfected and 57% (95% CI, −371% to 96%) among HIV-infected children. Among HIV-exposed but -uninfected children, effectiveness of ≥2 doses was 92% (95% CI, 47%–99%) against vaccine-serotype IPD. Effectiveness of ≥2 doses against all-serotype multidrug-resistant IPD was 96% (95% CI, 62%–100%) among HIV-uninfected children.
Conclusions. A 2 + 1 PCV7 schedule was effective in preventing vaccine-serotype IPD in HIV-uninfected and HIV-exposed, uninfected children. This finding supports the World Health Organization recommendation for this schedule as an alternative to a 3-dose primary series among HIV-uninfected individuals.
PMCID: PMC4144265  PMID: 24917657
children; HIV; pneumococcus; pneumococcal conjugate vaccine; South Africa
2.  Determining the Provincial and National Burden of Influenza-Associated Severe Acute Respiratory Illness in South Africa Using a Rapid Assessment Methodology 
PLoS ONE  2015;10(7):e0132078.
Local disease burden data are necessary to set national influenza vaccination policy. In 2010 the population of South Africa was 50 million and the HIV prevalence was 11%. We used a previously developed methodology to determine severe influenza burden in South Africa.
Hospitalized severe acute respiratory illness (SARI) incidence was calculated, stratified by HIV status, for four age groups using data from population-based surveillance in one site situated in Gauteng Province for 2009–2011. These rates were adjusted for each of the remaining 8 provinces based on their prevalence of risk factors for pneumonia and healthcare-seeking behavior. We estimated non-hospitalized influenza-associated SARI from healthcare utilization surveys at two sites and used the percent of SARI cases positive for influenza from sentinel surveillance to derive the influenza-associated SARI rate. We applied rates of hospitalized and non-hospitalized influenza-associated SARI to census data to calculate the national number of cases. The percent of SARI cases that tested positive for influenza ranged from 7–17% depending on age group, year, province and HIV status. In 2010, there were an estimated 21,555 total severe influenza cases in HIV-uninfected individuals and 13,876 in HIV-infected individuals. In 2011, there were an estimated 29,892 total severe influenza cases in HIV-uninfected individuals and 17,289 in HIV-infected individuals. The incidence of influenza-associated SARI was highest in children <5 years and was higher in HIV-infected than HIV-uninfected persons in all age groups. Influenza virus was associated with a substantial amount of severe disease, especially in young children and HIV-infected populations in South Africa.
PMCID: PMC4496064  PMID: 26154306
3.  Evaluation of influenza vaccine effectiveness and description of circulating strains in outpatient settings in South Africa, 2014 
The effectiveness of the trivalent seasonal influenza vaccine during the 2014 season in South Africa was assessed using a test-negative case–control study design including 472 cases and 362 controls. Influenza A(H3N2) was the dominant strain circulating. The overall vaccine effectiveness estimate, adjusted for age and underlying conditions, was 43·1% (95% CI: −26·8–74·5). 2014 H3N2 viruses from South Africa were mainly in sublineage 3C.3 with accumulation of amino acid changes that differentiate them from the vaccine strain in 3C.1.
PMCID: PMC4474497  PMID: 25865249
Effectiveness; influenza; vaccine
4.  Excess Mortality Associated with Influenza among Tuberculosis Deaths in South Africa, 1999–2009 
PLoS ONE  2015;10(6):e0129173.
Published data on the interaction between influenza and pulmonary tuberculosis (PTB) are limited. We aimed to estimate the influenza-associated mortality among individuals with PTB in South Africa from 1999–2009.
We modelled the excess influenza-associated mortality by applying Poisson regression models to monthly PTB and non-tuberculosis respiratory deaths, using laboratory-confirmed influenza as a covariate.
PTB deaths increased each winter, coinciding with influenza virus circulation. Among individuals of any age, mean annual influenza-associated PTB mortality rate was 164/100,000 person-years (n = 439). The rate of non-tuberculosis respiratory deaths was 27/100,000 (n = 1125) for HIV-infected and 5/100,000 (n = 2367) for HIV-uninfected individuals of all ages. Among individuals aged <65 years, influenza-associated PTB mortality risk was elevated compared to influenza-associated non-tuberculosis respiratory deaths in HIV-infected (relative risk (RR): 5.2; 95% CI: 4.6–5.9) and HIV-uninfected individuals (RR: 61.0; CI: 41.4–91.0). Among individuals aged ≥65 years, influenza-associated PTB mortality risk was elevated compared to influenza-associated non-tuberculosis respiratory deaths in HIV-uninfected individuals (RR: 13.0; 95% CI: 12.0–14.0).
We observed an increased risk of influenza-associated mortality in persons with PTB compared to non-tuberculosis respiratory deaths. If confirmed in other settings, our findings may support recommendations for active inclusion of patients with TB for influenza vaccination and empiric influenza anti-viral treatment of patients with TB during influenza epidemics.
PMCID: PMC4467974  PMID: 26076197
5.  Potential Impact of Co-Infections and Co-Morbidities Prevalent in Africa on Influenza Severity and Frequency: A Systematic Review 
PLoS ONE  2015;10(6):e0128580.
Infectious diseases and underlying medical conditions common to Africa may affect influenza frequency and severity. We conducted a systematic review of published studies on influenza and the following co-infections or co-morbidities that are prevalent in Africa: dengue, malaria, measles, meningococcus, Pneumocystis jirovecii pneumonia (PCP), hemoglobinopathies, and malnutrition. Articles were identified except for influenza and PCP. Very few studies were from Africa. Sickle cell disease, dengue, and measles co-infection were found to increase the severity of influenza disease, though this is based on few studies of dengue and measles and the measles study was of low quality. The frequency of influenza was increased among patients with sickle cell disease. Influenza infection increased the frequency of meningococcal disease. Studies on malaria and malnutrition found mixed results. Age-adjusted morbidity and mortality from influenza may be more common in Africa because infections and diseases common in the region lead to more severe outcomes and increase the influenza burden. However, gaps exist in our knowledge about these interactions.
PMCID: PMC4466242  PMID: 26068416
6.  Effectiveness and knowledge, attitudes and practices of seasonal influenza vaccine in primary healthcare settings in South Africa, 2010–2013 
Influenza vaccine effectiveness (VE) and coverage data for sub-Saharan Africa are scarce. Using a test-negative case–control design, we estimated influenza VE annually among individuals with influenza-like illness presenting to an outpatient sentinel surveillance programme in South Africa from 2010 to 2013. A knowledge, attitudes and practices (KAP) influenza vaccine survey of programme clinicians was conducted in 2013.
In total, 9420 patients were enrolled in surveillance of whom 5344 (56.7%) were included in the VE analysis: 2678 (50.1%) were classified as controls (influenza test-negative) and 2666 (49.9%) as cases (influenza test-positive).
Mean annual influenza vaccine coverage among controls was 4.5% for the four years. Annual VE estimates adjusted for age, underlying medical conditions and seasonality for 2010-2013 were 54.2% (95% confidence interval (CI): 2.4–78.6%), 57.1% (95% CI: 15.5–78.2%), 38.4% (95% CI: −71.7–78.1%) and 87.2% (95% CI: 67.2–95.0%), respectively. The KAP survey showed that >90% of clinicians were familiar with the indications for and the benefits of influenza vaccination.
Our study showed that the vaccine was significantly protective in 2010, 2011 and 2013, but not in 2012 when the circulating A(H3N2) strain showed genetic drift. Vaccine coverage was low despite good clinician knowledge of vaccination indications. Further studies are needed to investigate the reason for the low uptake of influenza vaccine.
PMCID: PMC4415698  PMID: 25677874
attitudes; Influenza-like illness; knowledge; practices; vaccine
7.  Deaths Associated with Respiratory Syncytial and Influenza Viruses among Persons ≥5 Years of Age in HIV-Prevalent Area, South Africa, 1998–20091 
Emerging Infectious Diseases  2015;21(4):600-608.
Mortality rates were higher among HIV-positive persons and older persons who had influenza.
Deaths Associated with Respiratory Viruses in HIV-Prevalent Area
We estimated deaths attributable to influenza and respiratory syncytial virus (RSV) among persons >5 years of age in South Africa during 1998–2009 by applying regression models to monthly deaths and laboratory surveillance data. Rates were expressed per 100,000 person-years. The mean annual number of seasonal influenza–associated deaths was 9,093 (rate 21.6). Persons >65 years of age and HIV-positive persons accounted for 50% (n = 4,552) and 28% (n = 2,564) of overall seasonal influenza-associated deaths, respectively. In 2009, we estimated 4,113 (rate 9.2) influenza A(H1N1)pdm09–associated deaths. The mean of annual RSV-associated deaths during the study period was 511 (rate 1.2); no RSV-associated deaths were estimated in persons >45 years of age. Our findings support the recommendation for influenza vaccination of older persons and HIV-positive persons. Surveillance for RSV should be strengthened to clarify the public health implications and severity of illness associated with RSV infection in South Africa.
PMCID: PMC4378466  PMID: 25811455
Influenza; viruses; respiratory syncytial virus; RSV; HIV; human immunodeficiency virus; mortality rates; deaths; South Africa
8.  Evaluation of Two Influenza Surveillance Systems in South Africa 
PLoS ONE  2015;10(3):e0120226.
The World Health Organisation recommends outpatient influenza-like illness (ILI) and inpatient severe acute respiratory illness (SARI) surveillance. We evaluated two influenza surveillance systems in South Africa: one for ILI and another for SARI.
The Viral Watch (VW) programme has collected virological influenza surveillance data voluntarily from patients with ILI since 1984 in private and public clinics in all 9 South African provinces. The SARI surveillance programme has collected epidemiological and virological influenza surveillance data since 2009 in public hospitals in 4 provinces by dedicated personnel. We compared nine surveillance system attributes from 2009–2012.
We analysed data from 18,293 SARI patients and 9,104 ILI patients. The annual proportion of samples testing positive for influenza was higher for VW (mean 41%) than SARI (mean 8%) and generally exceeded the seasonal threshold from May to September (VW: weeks 21–40; SARI: weeks 23–39). Data quality was a major strength of SARI (most data completion measures >90%; adherence to definitions: 88–89%) and a relative weakness of the VW programme (62% of forms complete, with limited epidemiologic data collected; adherence to definitions: 65–82%). Timeliness was a relative strength of both systems (e.g. both collected >93% of all respiratory specimens within 7 days of symptom onset). ILI surveillance was more nationally representative, financially sustainable and expandable than the SARI system. Though the SARI programme is not nationally representative, the high quality and detail of SARI data collection sheds light on the local burden and epidemiology of severe influenza-associated disease.
To best monitor influenza in South Africa, we propose that both ILI and SARI should be under surveillance. Improving ILI surveillance will require better quality and more systematic data collection, and SARI surveillance should be expanded to be more nationally representative, even if this requires scaling back on information gathered.
PMCID: PMC4379032  PMID: 25822719
9.  Mortality amongst Patients with Influenza-Associated Severe Acute Respiratory Illness, South Africa, 2009-2013 
PLoS ONE  2015;10(3):e0118884.
Data on the burden and risk groups for influenza-associated mortality from Africa are limited. We aimed to estimate the incidence and risk-factors for in-hospital influenza-associated severe acute respiratory illness (SARI) deaths.
Hospitalised patients with SARI were enrolled prospectively in four provinces of South Africa from 2009–2013. Using polymerase chain reaction, respiratory samples were tested for ten respiratory viruses and blood for pneumococcal DNA. The incidence of influenza-associated SARI deaths was estimated at one urban hospital with a defined catchment population.
We enrolled 1376 patients with influenza-associated SARI and 3% (41 of 1358 with available outcome data) died. In patients with available HIV-status, the case-fatality proportion (CFP) was higher in HIV-infected (5%, 22/419) than HIV-uninfected individuals (2%, 13/620; p = 0.006). CFPs varied by age group, and generally increased with increasing age amongst individuals >5 years (p<0.001). On multivariable analysis, factors associated with death were age-group 45–64 years (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.01–16.3) and ≥65 years (OR 6.5, 95%CI 1.2–34.3) compared to 1–4 year age-group who had the lowest CFP, HIV-infection (OR 2.9, 95%CI 1.1–7.8), underlying medical conditions other than HIV (OR 2.9, 95%CI 1.2–7.3) and pneumococcal co-infection (OR 4.1, 95%CI 1.5–11.2). The estimated incidence of influenza-associated SARI deaths per 100,000 population was highest in children <1 year (20.1, 95%CI 12.1–31.3) and adults aged 45–64 years (10.4, 95%CI 8.4–12.9). Adjusting for age, the rate of death was 20-fold (95%CI 15.0–27.8) higher in HIV-infected individuals than HIV-uninfected individuals.
Influenza causes substantial mortality in urban South Africa, particularly in infants aged <1 year and HIV-infected individuals. More widespread access to antiretroviral treatment and influenza vaccination may reduce this burden.
PMCID: PMC4365037  PMID: 25786103
10.  Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged ≥5 Years in a High HIV-Prevalence Setting, 2009–2012 
PLoS ONE  2015;10(2):e0117716.
There are few published studies describing severe acute respiratory illness (SARI) epidemiology amongst older children and adults from high HIV-prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged ≥5 years in South Africa.
We conducted prospective surveillance for individuals with SARI from 2009–2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators.
We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9% (600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13–19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR):1.7; 95%CI:1.1–2.7), have pneumococcal infection (OR 2.4; 95%CI:1.7–3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95%CI:1.2–2.2) and had a higher case-fatality ratio (8% vs 5%;OR1.7; 95%CI:1.2–2.3), but were less likely to be infected with influenza (OR 0.6; 95%CI:0.5–0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8;95%CI:1.3–2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95%CI:1.3–32.0) and supplemental-oxygen therapy (OR 2.6; 95%CI:2.1–3.2).
The burden of hospitalized SARI amongst individuals aged ≥5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting.
PMCID: PMC4337909  PMID: 25706880
11.  Influenza virus infection is associated with increased risk of death amongst patients hospitalized with confirmed pulmonary tuberculosis in South Africa, 2010–2011 
Data on the association between influenza and tuberculosis are limited. We describe the characteristics of patients with laboratory-confirmed tuberculosis, laboratory-confirmed influenza and tuberculosis-influenza co-infection.
Patients hospitalized with severe respiratory illness (acute and chronic) were enrolled prospectively in four provinces in South Africa. Naso/oropharyngeal specimens were tested for influenza virus by real time reverse transcriptase polymerase chain reaction. Tuberculosis testing was conducted as part of clinical management.
From June 2010 through December 2011, 8032 patients were enrolled and influenza testing was conducted on 7863 (98%). Influenza virus was detected in 765 (10%) patients. Among 2959 patients with tuberculosis and influenza results, 2227 (75%) were negative for both pathogens, 423 (14%) were positive for tuberculosis alone, 275 (9%) were positive for influenza alone and 34 (1%) had influenza and tuberculosis co-infection. On multivariable analysis amongst individuals with symptoms for ≥7 days, tuberculosis influenza co-infection was associated with increased risk of death, (adjusted relative risk ratio (aRRR) (6.1, 95% confidence interval (CI) 1.6-23.4), as compared to tuberculosis only infection. This association was not observed in individuals with symptoms for <7 days (aRRR.0.8, 95% CI 0.1-7.0).
Tuberculosis and influenza co-infection compared to tuberculosis single infection was associated with increased risk of death in individuals with symptoms ≥7 days. The potential public health impact of influenza vaccination among persons with laboratory-confirmed tuberculosis should be explored.
PMCID: PMC4316613  PMID: 25623944
Influenza; Tuberculosis; Co-infection; South Africa
12.  Hospitalizations associated with influenza and respiratory syncytial virus among patients attending a network of private hospitals in South Africa, 2007–2012 
BMC Infectious Diseases  2014;14:694.
Influenza and respiratory syncytial virus (RSV) infection are common causes of lower respiratory tract illness. Data on their burden in low and middle-income settings and from Africa are scarce. We aimed to estimate age-specific rates of hospitalization attributable to influenza and RSV among patients attending private hospitals in South Africa during 2007–2012.
We estimated annual age-specific rates of influenza- and RSV-associated hospitalization (that is respiratory hospitalizations likely due to influenza or RSV infection) by applying regression models to monthly administrative hospitalization data from a national private hospital group, using influenza and RSV surveillance data as covariates.
Estimated mean hospitalization rates associated with seasonal influenza were 75 (95% confidence interval (CI), 41–108) and 3 (95% CI, 2–5) per 100,000 person-years for all-respiratory and all-circulatory causes, respectively. Children <1 year and adults ≥75 years were the most affected, with influenza-associated all-respiratory hospitalization rates estimated at 255 (95% CI, 143–358) and 380 (95% CI, 227–506) per 100,000 person-years, respectively. Excess all-circulatory hospitalizations associated with seasonal influenza were only observed in adults ≥65 years. Annual hospitalization rates associated with RSV averaged an estimate of 223 (95% CI, 128–317) per 100,000 person-years for all-respiratory causes. Among children <1 year, RSV-associated all-respiratory hospitalization rate of 7,601 (95% CI, 4,312-10,817) per 100,000 person-years was estimated.
Influenza and RSV substantially contributed to hospitalizations over the study period.
PMCID: PMC4278267  PMID: 25510622
Influenza virus; Respiratory syncytial virus; Hospitalization; South Africa
13.  Factors Associated with Ceftriaxone Nonsusceptibility of Streptococcus pneumoniae: Analysis of South African National Surveillance Data, 2003 to 2010 
It is important to monitor β-lactam antimicrobial nonsusceptibility trends for Streptococcus pneumoniae to inform empirical treatment guidelines. In this study, we describe penicillin and ceftriaxone susceptibility trends using national laboratory-based pneumococcal surveillance data from 2003 to 2010. A sentinel enhanced-site patient subset (2009 to 2010) contributed to the risk factor and mortality analyses. We included 9,218 invasive pneumococcal disease (IPD) cases for trend analyses and 2,854 IPD cases for risk factor and mortality analyses. Overall, we detected no significant changes in penicillin (patients <5 years of age, P = 0.50; patients ≥5 years of age, P = 0.05) or ceftriaxone nonsusceptibility rates (patients <5 years of age, P = 0.21; patients ≥5 years of age, P = 0.60). Factors associated with ceftriaxone nonsusceptibility on multivariate analysis were an age of <5 years (<1 year of age: adjusted odds ratio [aOR], 2.87; 95% confidence interval [CI], 1.70 to 4.86; 1 to 4 years of age: aOR, 2.58; 95% CI, 1.53 to 4.35, versus 25 to 44 years of age), province (Gauteng [aOR, 2.46; 95% CI, 1.26 to 4.84], and Northern Cape [aOR, 4.52; 95% CI, 1.95 to 10.52] versus KwaZulu-Natal), β-lactam use within 24 h preceding admission (aOR, 2.52; 95% CI, 1.41 to 4.53), and 13-valent vaccine serotypes (aOR, 51.64; 95% CI, 7.18 to 371.71). Among patients ≥5 years of age with meningitis who were treated according to current guidelines, HIV-infected patients (aOR, 2.94; 95% CI, 1.32 to 6.54) and patients infected with ceftriaxone-nonsusceptible isolates (aOR, 3.17; 95% CI, 1.27 to 7.89) had increased mortality rates. Among children <5 years of age with meningitis, mortality was increased in HIV-infected patients (aOR, 3.04; 95% CI, 1.40 to 6.56) but not in those with ceftriaxone-nonsusceptible isolates. Penicillin and ceftriaxone nonsusceptibility remained stable over the study period. Ceftriaxone nonsusceptibility was associated with increased mortality among patients ≥5 years of age with meningitis. The introduction of a pneumococcal conjugate vaccine may reduce ceftriaxone-nonsusceptible meningitis.
PMCID: PMC4068496  PMID: 24687499
14.  Genetic diversity and molecular epidemiology of human rhinoviruses in South Africa 
Rhinoviruses (RV) are a well-established cause of respiratory illness. RV-C has been associated with more severe illness. We aimed to characterize and compare the clinical presentations and disease severity of different RV type circulating in South Africa.
We performed two analyses of RV-positive specimens identified through surveillance in South Africa across all age groups. First, RV-positive specimens identified through severe acute respiratory illness (SARI) surveillance in four provinces was randomly selected from 2009 to 2010 for molecular characterization. Second, RV-positive specimens identified through SARI, influenza-like illness (ILI) and control surveillance at hospitals and outpatient clinics in during 2012–2013 were used to determine the association of RV type with severe disease. Selected specimens were sequenced, and phylogenetic analysis was performed.
Among the 599 sequenced specimens from 2009 to 2010 and 2012 to 2013, RV-A (285, 48%) and RV-C (247, 41%) were more commonly identified than RV-B (67, 11%), with no seasonality and a high genetic diversity. A higher prevalence of RV infection was identified in cases with SARI [515/962 (26%); aRRR = 1·6; 95% CI 1·21; 2·2] and ILI [356/962 (28%); aRRR = 1·9; 95% CI 1·37; 2·6] compared with asymptomatic controls (91/962, 22%). There was no difference in disease severity between the different type when comparing SARI, ILI and controls.
All three type of RV were identified in South Africa, although RV-A and RV-C were more common than RV-B. RV was associated with symptomatic respiratory illness; however, there was no association between RV type and disease severity.
PMCID: PMC4181821  PMID: 24990601
Disease association; genetic diversity; rhinovirus; South Africa
15.  Epidemiology of Influenza Virus Types and Subtypes in South Africa, 2009–20121 
Emerging Infectious Diseases  2014;20(7):1149-1156.
Patient age and co-infections, but not disease severity, were associated with virus type and subtype.
To determine clinical and epidemiologic differences between influenza caused by different virus types and subtypes, we identified patients and tested specimens. Patients were children and adults hospitalized with confirmed influenza and severe acute respiratory illness (SARI) identified through active, prospective, hospital-based surveillance from 2009–2012 in South Africa. Respiratory specimens were tested, typed, and subtyped for influenza virus by PCR. Of 16,005 SARI patients tested, 1,239 (8%) were positive for influenza virus. Patient age and co-infections varied according to virus type and subtype, but disease severity did not. Case-patients with influenza B were more likely than patients with influenza A to be HIV infected. A higher proportion of case-patients infected during the first wave of the 2009 influenza pandemic were 5–24 years of age (19%) than were patients infected during the second wave (9%). Although clinical differences exist, treatment recommendations do not differ according to subtype; prevention through vaccination is recommended.
PMCID: PMC4073865  PMID: 24960314
influenza; influenza A; influenza B; H3N2; H1N1; types; subtypes; pneumonia; South Africa; viruses
16.  Influenza Epidemiology and Vaccine Effectiveness among Patients with Influenza-Like Illness, Viral Watch Sentinel Sites, South Africa, 2005–2009 
PLoS ONE  2014;9(4):e94681.
There is limited data on the epidemiology of influenza and few published estimates of influenza vaccine effectiveness (VE) from Africa. In April 2009, a new influenza virus strain infecting humans was identified and rapidly spread globally. We compared the characteristics of patients ill with influenza A(H1N1)pdm09 virus to those ill with seasonal influenza and estimated influenza vaccine effectiveness during five influenza seasons (2005–2009) in South Africa.
Epidemiological data and throat and/or nasal swabs were collected from patients with influenza-like illness (ILI) at sentinel sites. Samples were tested for seasonal influenza viruses using culture, haemagglutination inhibition tests and/or polymerase chain reaction (PCR) and for influenza A(H1N1)pdm09 by real-time PCR. For the vaccine effectiveness (VE) analysis we considered patients testing positive for influenza A and/or B as cases and those testing negative for influenza as controls. Age-adjusted VE was calculated as 1-odds ratio for influenza in vaccinated and non-vaccinated individuals.
From 2005 through 2009 we identified 3,717 influenza case-patients. The median age was significantly lower among patients infected with influenza A(H1N1)pdm09 virus than those with seasonal influenza, 17 and 27 years respectively (p<0.001). The vaccine coverage during the influenza season ranged from 3.4% in 2009 to 5.1% in 2006 and was higher in the ≥50 years (range 6.9% in 2008 to 13.2% in 2006) than in the <50 years age group (range 2.2% in 2007 to 3.7% in 2006). The age-adjusted VE estimates for seasonal influenza were 48.6% (4.9%, 73.2%); −14.2% (−9.7%, 34.8%); 12.0% (−70.4%, 55.4%); 67.4% (12.4%, 90.3%) and 29.6% (−21.5%, 60.1%) from 2005 to 2009 respectively. For the A(H1N1)pdm09 season, the efficacy of seasonal vaccine was −6.4% (−93.5%, 43.3%).
Influenza vaccine demonstrated a significant protective effect in two of the five years evaluated. Low vaccine coverage may have reduced power to estimate vaccine effectiveness.
PMCID: PMC3988097  PMID: 24736452
17.  Introduction of 2009 Pandemic Influenza A Virus Subtype H1N1 Into South Africa: Clinical Presentation, Epidemiology, and Transmissibility of the First 100 Cases 
The Journal of Infectious Diseases  2012;206(Suppl 1):S148-S153.
Background. We documented the introduction of 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) into South Africa and describe its clinical presentation, epidemiology, and transmissibility.
Methods. We conducted a prospective descriptive study of the first 100 laboratory-confirmed cases of A(H1N1)pdm09 infections identified through active case finding and surveillance. Infected patients and the attending clinicians were interviewed, and close contacts were followed up to investigate household transmission.
Findings. The first case was confirmed on 14 June 2009, and by 15 July 2009, 100 cases were diagnosed. Forty-two percent of patients reported international travel within 7 days prior to onset of illness. Patients ranged in age from 4 to 70 years (median age, 21.5 years). Seventeen percent of household contacts developed influenza-like illness, and 10% of household contacts had laboratory-confirmed A(H1N1)pdm09 infection. We found a mean serial interval (± SD) of 2.3 ± 1.3 days (range, 1–5 days) between successive laboratory-confirmed cases in the transmission chain.
Conclusions. A(H1N1)pdm09 established itself rapidly in South Africa. Transmissibility of the virus was comparable to observations from outside of Africa and to seasonal influenza virus strains.
PMCID: PMC3572882  PMID: 23169962
18.  Severe Influenza-associated Respiratory Infection in High HIV Prevalence Setting, South Africa, 2009–2011 
Emerging Infectious Diseases  2013;19(11):1766-1774.
Data on influenza epidemiology in HIV-infected persons are limited, particularly for sub-Saharan Africa, where HIV infection is widespread. We tested respiratory and blood samples from patients with acute lower respiratory tract infections hospitalized in South Africa during 2009–2011 for viral and pneumococcal infections. Influenza was identified in 9% (1,056/11,925) of patients enrolled; among influenza case-patients, 358 (44%) of the 819 who were tested were infected with HIV. Influenza-associated acute lower respiratory tract infection incidence was 4–8 times greater for HIV-infected (186–228/100,000) than for HIV-uninfected persons (26–54/100,000). Furthermore, multivariable analysis showed HIV-infected patients were more likely to have pneumococcal co-infection; to be infected with influenza type B compared with type A; to be hospitalized for 2–7 days or >7 days; and to die from their illness. These findings indicate that HIV-infected persons are at greater risk for severe illnesses related to influenza and thus should be prioritized for influenza vaccination.
PMCID: PMC3837669  PMID: 24209781
influenza; HIV; AIDS; adults; children; pneumonia; pneumococcal; South Africa; viruses; vaccination; lower respiratory tract infection; respiratory infections; co-infection; bacteria; pneumoccocus
19.  Influenza-Related Mortality Among Adults Aged 25–54 Years With AIDS in South Africa and the United States of America 
In the absence of highly active therapy antiretroviral (HAART), adults with AIDS experience substantially elevated influenza-associated mortality in South Africa and the United States. This elevated mortality risk declined with widespread HAART introduction in the United States but did not disappear entirely. These data support increased access to HAART and influenza vaccination for human immunodeficiency virus–infected adults globally.
Background. Data are limited on human immunodeficiency virus (HIV)–associated influenza burden in sub-Saharan Africa and the impact of highly active antiretroviral therapy (HAART). We compared influenza-related mortality in adults with AIDS in South Africa and the United States in the pre-HAART era and evaluated mortality trends after HAART introduction in the United States.
Methods. Monthly all-cause and pneumonia and influenza (P&I) mortality rates were compiled for adults with AIDS aged 25–54 years in South Africa (1998–2005) and the United States (pre-HAART era, 1987–1994; HAART era, 1997–2005). We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods. Influenza-related mortality rates in adults with AIDS were compared with rates for age peers in the general population and adults ≥65 years old.
Results. In the United States before HAART, influenza-related mortality rates in adults with AIDS were 150 (95% confidence interval [CI], 49–460) and 208 (95% CI, 74–583) times greater than in the general population for all-cause and P&I deaths, respectively, and 2.5 (95% CI, 0.9–7.2) and 4.1 (95% CI, 1.4–13) times higher than in elderly adults. After HAART introduction , influenza-related mortality in adults with AIDS dropped 3–6-fold but remained elevated compared with the general population (all-cause relative risk [RR], 44 [95% CI, 16–121]); P&I RR, 73 [95% CI, 47–113]). Influenza-related mortality in South African adults with AIDS in recent years was similar to that in the United States in the pre-HAART era.
Conclusions. Adults with AIDS experience substantially elevated influenza-associated mortality, which declines with widespread HAART introduction but does not disappear. These data support increased access to HAART and influenza vaccination for HIV-infected adults.
PMCID: PMC3657519  PMID: 22715173
20.  Survey non-response in an internet-mediated, longitudinal autism research study 
To evaluate non-response rates to follow-up online surveys using a prospective cohort of parents raising at least one child with an autism spectrum disorder. A secondary objective was to investigate predictors of non-response over time.
Materials and Methods
Data were collected from a US-based online research database, the Interactive Autism Network (IAN). A total of 19 497 youths, aged 1.9–19 years (mean 9 years, SD 3.94), were included in the present study. Response to three follow-up surveys, solicited from parents after baseline enrollment, served as the outcome measures. Multivariate binary logistic regression models were then used to examine predictors of non-response.
31 216 survey instances were examined, of which 8772 or 28.1% were partly or completely responded to. Results from the multivariate model found non-response of baseline surveys (OR 28.0), years since enrollment in the online protocol (OR 2.06), and numerous sociodemographic characteristics were associated with non-response to follow-up surveys (all p<0.05).
Consistent with the current literature, response rates to online surveys were somewhat low. While many demographic characteristics were associated with non-response, time since registration and participation at baseline played the greatest role in predicting follow-up survey non-response.
An important hazard to the generalizability of findings from research is non-response bias; however, little is known about this problem in longitudinal internet-mediated research (IMR). This study sheds new light on important predictors of longitudinal response rates that should be considered before launching a prospective IMR study.
PMCID: PMC3384126  PMID: 22539079
ASD; autism; decision modeling; education; informatics; internet-mediated research; online survey research; public health informatics; survey non-response
21.  Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis 
Lancet  2013;381(9875):1380-1390.
The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010.
We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies.
We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3–13·9 million) episodes of severe and 3·0 million (2·1–4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265 000 (95% CI 160 000–450 000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals.
Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities.
PMCID: PMC3986472  PMID: 23369797
22.  Risk Factors for Multidrug-Resistant Invasive Pneumococcal Disease in South Africa, a Setting with High HIV Prevalence, in the Prevaccine Era from 2003 to 2008 
Antimicrobial Agents and Chemotherapy  2012;56(10):5088-5095.
The emergence of multidrug-resistant (MDR) Streptococcus pneumoniae complicates disease management. We aimed to determine risk factors associated with MDR invasive pneumococcal disease (IPD) in South Africa and evaluate the potential for vaccination to reduce disease burden. IPD data collected by laboratory-based surveillance from 2003 through 2008 were analyzed. Multidrug resistance was defined as nonsusceptibility to any three or more different antibiotic classes. Risk factors for multidrug resistance were evaluated using multivariable logistic regression. Of 20,100 cases of IPD identified, 3,708 (18%) had MDR isolates, with the proportion increasing from 16% (461/2,891) to 20% (648/3,326) (P < 0.001) over the study period. Serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) accounted for 94% of MDR strains. Significant risk factors for MDR IPD included PCV13 (1,486/6,407; odds ratio [OR] of 6.3; 95% confidence interval [CI] of 5.0 to 7.9) and pediatric (3,382/9,980; OR of 12.8; 95% CI of 10.6 to 15.4) serotypes, age of <5 (802/3,110; OR of 2.0; 95% CI of 1.8 to 2.3) or ≥65 (39/239; OR of 1.5; 95% CI of 1.0 to 2.2) years versus age of 15 to 64 years, HIV infection (975/4,636; OR of 1.5; 95% CI of 1.2 to 1.8), previous antibiotic use (242/803; OR of 1.7; 95% CI of 1.4 to 2.1), previous hospital admissions (579/2,450; OR of 1.2; 95% CI of 1.03 to 1.4), urban location (883/4,375; OR of 2.0; 95% CI of 1.1 to 3.5), and tuberculosis treatment (246/1,021; OR of 1.2; 95% CI of 1.03 to 1.5). MDR IPD prevalence increased over the study period. The effect of many of the MDR risk factors could be reduced by more judicious use of antibiotics. Because PCV13 serotypes account for most MDR infections, pneumococcal vaccination may reduce the prevalence of multidrug resistance.
PMCID: PMC3457358  PMID: 22802256
23.  Measles Outbreak in South Africa: Epidemiology of Laboratory-Confirmed Measles Cases and Assessment of Intervention, 2009–2011 
PLoS ONE  2013;8(2):e55682.
Since 1995, measles vaccination at nine and 18 months has been routine in South Africa; however, coverage seldom reached >95%. We describe the epidemiology of laboratory-confirmed measles case-patients and assess the impact of the nationwide mass vaccination campaign during the 2009 to 2011 measles outbreak in South Africa.
Serum specimens collected from patients with suspected-measles were tested for measles-specific IgM antibodies using an enzyme-linked immunosorbent assay and genotypes of a subset were determined. To estimate the impact of the nationwide mass vaccination campaign, we compared incidence in the seven months pre- (1 September 2009–11 April 2010) and seven months post-vaccination campaign (24 May 2010–31 December 2010) periods in seven provinces of South Africa.
A total of 18,431 laboratory-confirmed measles case-patients were reported from all nine provinces of South Africa (cumulative incidence 37 per 100,000 population). The highest cumulative incidence per 100,000 population was in children aged <1 year (603), distributed as follows: <6 months (302/100,000), 6 to 8 months (1083/100,000) and 9 to 11 months (724/100,000). Forty eight percent of case-patients were ≥5 years (cumulative incidence 54/100,000). Cumulative incidence decreased with increasing age to 2/100,000 in persons ≥40 years. A single strain of measles virus (genotype B3) circulated throughout the outbreak. Prior to the vaccination campaign, cumulative incidence in the targeted vs. non-targeted age group was 5.9-fold higher, decreasing to 1.7 fold following the campaign (P<0.001) and an estimated 1,380 laboratory-confirmed measles case-patients were prevented.
We observed a reduction in measles incidence following the nationwide mass vaccination campaign even though it was conducted approximately one year after the outbreak started. A booster dose at school entry may be of value given the high incidence in persons >5 years.
PMCID: PMC3577838  PMID: 23437059
24.  Reproductive Number and Serial Interval of the First Wave of Influenza A(H1N1)pdm09 Virus in South Africa 
PLoS ONE  2012;7(11):e49482.
Describing transmissibility parameters of past pandemics from diverse geographic sites remains critical to planning responses to future outbreaks. We characterize the transmissibility of influenza A(H1N1)pdm09 (hereafter pH1N1) in South Africa during 2009 by estimating the serial interval (SI), the initial effective reproductive number (initial Rt) and the temporal variation of Rt.
We make use of data from a central registry of all pH1N1 laboratory-confirmed cases detected throughout South Africa. Whenever date of symptom onset is missing, we estimate it from the date of specimen collection using a multiple imputation approach repeated 100 times for each missing value. We apply a likelihood-based method (method 1) for simultaneous estimation of initial Rt and the SI; estimate initial Rt from SI distributions established from prior field studies (method 2); and the Wallinga and Teunis method (method 3) to model the temporal variation of Rt.
12,360 confirmed pH1N1 cases were reported in the central registry. During the period of exponential growth of the epidemic (June 21 to August 3, 2009), we simultaneously estimate a mean Rt of 1.47 (95% CI: 1.30–1.72) and mean SI of 2.78 days (95% CI: 1.80–3.75) (method 1). Field studies found a mean SI of 2.3 days between primary cases and laboratory-confirmed secondary cases, and 2.7 days when considering both suspected and confirmed secondary cases. Incorporating the SI estimate from field studies using laboratory-confirmed cases, we found an initial Rt of 1.43 (95% CI: 1.38–1.49) (method 2). The mean Rt peaked at 2.91 (95% CI: 0.85–2.91) on June 21, as the epidemic commenced, and Rt>1 was sustained until August 22 (method 3).
Transmissibility characteristics of pH1N1 in South Africa are similar to estimates reported by countries outside of Africa. Estimations using the likelihood-based method are in agreement with field findings.
PMCID: PMC3500305  PMID: 23166682
25.  Trimethoprim-Sulfamethoxazole Prophylaxis and Antibiotic Nonsusceptibility in Invasive Pneumococcal Disease 
Among 5,043 invasive pneumococcal disease (IPD) isolates identified through South African national surveillance from 2003 to 2007, we estimated the effect of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis on antimicrobial resistance. Patients on TMP-SMX prophylaxis were more likely to have a pneumococcal isolate nonsusceptible to TMP-SMX, penicillin, and rifampin. TMP-SMX nonsusceptibility was associated with nonsusceptibility to penicillin, erythromycin, and rifampin and multidrug resistance. This study informs empirical treatment of suspected IPD in patients with a history of TMP-SMX use.
PMCID: PMC3294938  PMID: 22232291

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