Johanna M. McAnerney

Mortality Associated With Seasonal and Pandemic Influenza and Respiratory Syncytial Virus Among Children <5 Years of Age in a High HIV Prevalence Setting—South Africa, 1998–2009

BACKGROUND There are few published data describing the mortality burden associated with influenza and respiratory syncytial virus (RSV) infection in children in low- and middle-income countries and particularly from Africa and settings with high prevalence of human immunodeficiency virus (HIV). METHODS We modeled the excess mortality attributable to influenza (seasonal and pandemic) and RSV infection by applying Poisson regression models to monthly all-respiratory and pneumonia and influenza deaths, using national influenza and RSV laboratory surveillance data as covariates. In addition, we estimated the seasonal influenza- and RSV-associated deaths among HIV-infected and -uninfected children using Poisson regression models that incorporated HIV prevalence and highly active antiretroviral therapy coverage as covariates. RESULTS In children <5 years of age, the mean annual numbers of seasonal influenza- and RSV-associated all-respiratory deaths were 452 (8 per 100 000 person-years [PY]) and 546 (10 per 100 000 PY), respectively. Infants <1 year of age experienced higher mortality rates compared with children 1-4 years of age for both influenza (22 vs 5 per 100 000 PY) and RSV (35 vs 4 per 100 000 PY). HIV-infected compared with HIV-uninfected children <5 years of age were at increased risk of death associated with influenza (age-adjusted relative risk [aRR], 11.5; 95% confidence interval [CI], 9.6-12.6) and RSV (aRR, 8.1; 95% CI, 6.9-9.3) infection. In 2009, we estimated 549 (11 per 100 000 PY) all-respiratory influenza A(H1N1)pdm09-associated deaths among children aged <5 years. CONCLUSIONS Our findings support increased research efforts to guide and prioritize interventions such as influenza vaccination and HIV prevention in low- and middle-income countries with high HIV prevalence such as South Africa.

Twenty-five Years of Outpatient Influenza Surveillance in South Africa, 1984–2008

INTRODUCTION Understanding the seasonality of influenza can help inform prevention and clinical treatment strategies. The aim of this manuscript is to describe the trends and epidemiology of outpatient influenza in South Africa prior to the influenza A(H1N1) pandemic. METHODS Throughout each year, participating healthcare practitioners sent throat swabs from patients with influenza-like illness (ILI) to the National Institute for Communicable Diseases for influenza testing by immunofluorescence and viral culture through the Viral Watch influenza surveillance program. RESULTS From 1984 to 2004, participating sites were restricted to 1 province and the annual number of specimens ranged from 91 to 534. In 2005 the program was expanded. By 2008 the program included all 9 provinces; 1276 specimens were submitted that year. The mean week of onset was the first week of June and the mean peak was the first week of July. The duration of the season ranged from 6 to 18 weeks with a mean of 10 weeks. The mean annual influenza detection rate was 28% (range, 23%-41%). Influenza A(H3N2) predominated in 14 (56%) of the 25 years, seasonal influenza A(H1N1) in 7 (28%), and influenza B in 2 (8%), and in 2 years multiple types cocirculated. CONCLUSIONS The program has provided valuable data on the timing of the influenza season each year that can be useful to direct the timing of vaccination and assist clinicians in deciding whether to prescribe empirical antiviral therapy.

Deaths Associated with Respiratory Syncytial and Influenza Viruses among Persons ≥5 Years of Age in HIV-Prevalent Area, South Africa, 1998–20091

Mortality rates were higher among HIV-positive persons and older persons who had influenza. Deaths Associated with Respiratory Viruses in HIV-Prevalent Area

Measles Outbreak in South Africa: Epidemiology of Laboratory-Confirmed Measles Cases and Assessment of Intervention, 2009–2011

Background 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. Methods 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. Results 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. Conclusion 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.

Effectiveness of seasonal influenza vaccination in community-dwelling elderly people: an individual participant data meta-analysis of test-negative design case-control studies

BACKGROUND Several aggregate data meta-analyses have provided estimates of the effectiveness of influenza vaccination in community-dwelling elderly people. However, these studies ignored the effects of patient-level confounders such as sex, age, and chronic diseases that could bias effectiveness estimates. We aimed to assess the confounder-adjusted effectiveness of influenza vaccines on laboratory-confirmed influenza among elderly people by conducting a global individual participant data meta-analysis. METHODS In this individual participant data meta-analysis, we considered studies included in a previously conducted aggregate data meta-analysis that included test-negative design case-control studies published up to July 13, 2014. We contacted all authors of the included studies on Dec 1, 2014, to request individual participant data. Patients were excluded if their unique identifier was missing, their vaccination status was unknown, their outcome status was unknown, or they had had suspected influenza infection more than once in the same influenza season. Cases were patients with influenza-like illness symptoms who tested positive for at least one of A H1N1, A H1N1 pdm09, A H3N2, or B viruses; controls were patients with influenza-like illness symptoms who tested negative for these virus types or subtypes. Influenza vaccine effectiveness against overall and subtype-specific laboratory-confirmed influenza were the primary and secondary outcomes. We used a generalised linear mixed model to calculate adjusted vaccine effectiveness according to vaccine match to the circulating strains of influenza virus and intensity of the virus activity (epidemic or non-epidemic). Vaccine effectiveness was defined as the relative reduction in risk of laboratory-confirmed influenza in vaccinated patients compared with unvaccinated patients. We did subgroup analyses to estimate vaccine effectiveness according to hemisphere, age category, and health status. FINDINGS We received 23 of the 53 datasets included in the aggregate data meta-analysis. Furthermore, six additional datasets were provided by data collaborators, which resulted in individual participant data for a total of 5210 participants. A total of 4975 patients had the required data for analysis. Of these, 3146 (63%) were controls and 1829 (37%) were cases. Influenza vaccination was significantly effective during epidemic seasons irrespective of vaccine match status (matched adjusted vaccine effectiveness 44·38%, 95% CI 22·63-60·01; mismatched adjusted vaccine effectiveness 20·00%, 95% CI 3·46-33·68; analyses in the imputed dataset). Seasonal influenza vaccination did not show significant effectiveness during non-epidemic seasons. We found substantial variation in vaccine effectiveness across virus types and subtypes, with the highest estimate for A H1N1 pdm09 (53·19%, 10·25-75·58) and the lowest estimate for B virus types (-1·52%, -39·58 to 26·16). Although we observed no significant differences between subgroups in each category (hemisphere, age, and health status), influenza vaccination showed a protective effect among elderly people with cardiovascular disease, lung disease, or aged 75 years and younger. INTERPRETATION Influenza vaccination is moderately effective against laboratory-confirmed influenza in elderly people during epidemic seasons. More research is needed to investigate factors affecting vaccine protection (eg, brand-specific or type-specific vaccine effectiveness and repeated annual vaccination) in elderly people. FUNDING University Medical Center Groningen.

Influenza Epidemiology and Vaccine Effectiveness among Patients with Influenza-Like Illness, Viral Watch Sentinel Sites, South Africa, 2005–2009

Background 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. Methods 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. Results 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%). Conclusion 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.

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.

Rubella in South Africa : an impending Greek tragedy?

Background . The incidence of congenital rubella syndrome (CRS) is unknown in South Africa. There is evidence that it may be significant and largely undetected, particularly in the upper socio-economic group. This may be due to incomplete routine administration of MMR vaccine in infancy and a build-up of susceptible females reaching the childbearing age group who could be exposed to the extensive reservoir of virus in the unimmunised public sector of the population. Objective . To assess the extent of the immunity gap to rubella by testing for protective IgG antibodies and the incidence of rubella infection by testing for IgM antibodies in sera. The data obtained would also be used to model the extent of CRS. Design . Residual laboratory serum specimens from public and private laboratories were serologically tested for rubella IgG antibodies to investigate the immunity gap in the population and IgM antibodies in sera collected from the measles rashlike illness surveillance programme. Modelling exercises calculated the force of infection and the predicted incidence of CRS in South Africa. Results . The serological immunity gap was significantly greater in the private sector specimens compared with the public sector – 10.7% versus 5.4%, respectively. In most years rubella caused much more rash-like illness than measles, with a significant number (5.1 - 9.6%) of rubella-positive IgM specimens occurring in women of childbearing age. Conclusion . Modelling of the data suggests that the extent of CRS may be grossly underestimated in South Africa. Approximately 654 cases are calculated to occur every year. It is suggested that selective immunisation of girls before puberty should be instituted together with a routine rubella immunisation programme of infants to forestall a possible future outbreak of CRS, as occurred in Greece in 1993.

Excess Mortality Associated with Influenza among Tuberculosis Deaths in South Africa, 1999-2009.

Background 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. Methods 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. Results 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). Conclusion 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.

Temporal Association in Hospitalizations for Tuberculosis, Invasive Pneumococcal Disease and Influenza Virus Illness in South African Children

Introduction The seasonal variability in hospitalization for tuberculosis may in part relate to super-imposed bacterial or predisposing respiratory viral infections. We aimed to study the temporal association between hospitalization for culture-confirmed pulmonary tuberculosis (PTB), invasive pneumococcal disease (IPD) and influenza virus epidemics in South African children. Methods We undertook a retrospective analysis which examined seasonal trends, from 2005 to 2008, for hospitalization for culture-confirmed PTB and IPD among children in relation to the influenza epidemics in Soweto, South Africa. Original time-series of the influenza virus epidemics and hospitalization rates for PTB and IPD were decomposed into three components: a trend cycle component, a seasonal component and an irregular component using the X-11 seasonal adjustment method. To compare the seasonality amongst the three series, the trend and irregular components were removed and only seasonal components examined. Results Across the study period, the influenza virus epidemics peaked during May to July (winter) months, which was closely followed by an increase in the incidence of hospitalization for IPD (August to October) and PTB (August to November). Discussion Within- and between-year temporal changes associated with childhood TB hospitalization may in part be driven by factors which influence temporal changes in pneumococcal disease, including potential variability in the severity of influenza virus epidemics in temperate climates. The dynamics of the interplay between the host and these infectious agents appears to be complex and multifactorial.