Stefano Tempia

Influenza Surveillance in 15 Countries in Africa, 2006-2010

BACKGROUND In response to the potential threat of an influenza pandemic, several international institutions and governments, in partnership with African countries, invested in the development of epidemiologic and laboratory influenza surveillance capacity in Africa and the African Network of Influenza Surveillance and Epidemiology (ANISE) was formed. METHODS We used a standardized form to collect information on influenza surveillance system characteristics, the number and percent of influenza-positive patients with influenza-like illness (ILI), or severe acute respiratory infection (SARI) and virologic data from countries participating in ANISE. RESULTS Between 2006 and 2010, the number of ILI and SARI sites in 15 African countries increased from 21 to 127 and from 2 to 98, respectively. Children 0-4 years accounted for 48% of all ILI and SARI cases of which 22% and 10%, respectively, were positive for influenza. Influenza peaks were generally discernible in North and South Africa. Substantial cocirculation of influenza A and B occurred most years. CONCLUSIONS Influenza is a major cause of respiratory illness in Africa, especially in children. Further strengthening influenza surveillance, along with conducting special studies on influenza burden, cost of illness, and role of other respiratory pathogens will help detect novel influenza viruses and inform and develop targeted influenza prevention policy decisions in the region.

High Nasopharyngeal Pneumococcal Density, Increased by Viral Coinfection, Is Associated With Invasive Pneumococcal Pneumonia

BACKGROUND We identified factors associated with pneumococcal colonization, high colonization density, and invasive pneumococcal pneumonia among patients hospitalized with acute lower respiratory tract infections (ALRTIs). METHODS In 2010, 4025 cases were enrolled in surveillance in South Africa. A total of 969 of 4025 systematically selected nasopharyngeal-oropharyngeal specimens (24%) were tested for respiratory viruses and Streptococcus pneumoniae by real-time polymerase chain reaction. Of these, 749 (77%) had blood tested for S. pneumoniae. RESULTS Pneumococcal colonization was detected in 55% of cases (534 of 969). On multivariable analysis that controlled for age and tuberculosis treatment, infection with influenza virus (adjusted odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.5), adenovirus (adjusted OR, 1.7; 95% CI, 1.1-2.7), rhinovirus (adjusted OR, 1.6; 95% CI, 1.1-2.3), and human immunodeficiency virus (HIV; adjusted OR, 1.6; 95% CI, 1.1-2.4) were associated with pneumococcal colonization. High colonization density was associated with respiratory virus coinfection (adjusted OR, 1.7; 95% CI, 1.1-2.6) and invasive pneumococcal pneumonia (adjusted OR, 2.3; 95% CI, 1.3-4.0), after adjustment for age and sex. Seven percent (52 of 749) had pneumococci detected in blood. On multivariable analysis among colonized cases, invasive pneumococcal pneumonia was associated with HIV (adjusted OR, 3.2; 95% CI, 1.4-7.5), influenza virus (adjusted OR, 8.2; 95% CI, 2.7-25.0), high colonization density (adjusted OR, 18.7; 95% CI, 2.3-155.1), and ≥5 days of hospitalization (adjusted OR, 3.7; 95% CI, 1.7-8.2). CONCLUSIONS Respiratory virus infection was associated with elevated colonization density and, in turn, invasive pneumococcal pneumonia.

Severe influenza-associated respiratory infection in high HIV prevalence setting, South Africa, 2009-2011.

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.

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.

Replacement and Positive Evolution of Subtype A and B Respiratory Syncytial Virus G-Protein Genotypes From 1997–2012 in South Africa

BACKGROUND Of the respiratory syncytial virus (RSV) genotypes previously described in South Africa during 1997-2002, only GA2 and GA5 persisted until 2006, with BA having replaced all previous RSV-B genotypes. This poses the question whether RSV-A is more stable than RSV-B and whether positive selection drives evolution of genotypes. METHODS RSV-positive specimens were randomly selected during 2009-2012, subtyped, sequenced, and compared to RSV recovered from specimens obtained during 1997-2001 and 2006-2009. Bayesian phylogenetic analysis was performed on the G-protein. RESULTS Phylogenetic analysis indicated that RSV-A genotype GA2 dissolved to form SAA2 (unique to South Africa), NA1 and NA2 (identified in Japan), and ON1 (identified in Canada and having a 72-bp insertion) and that GA5 drifted from 1999-2012 to form 3 subgenotypes (GA5 I-III). RSV-B genotypes all had the 60-bp insertion typical of BA genotypes but clustered into subgenotypes BA8-10. Positive selection was identified in the G-protein of both subtypes, but RSV-As rate of evolution was slower than that of RSV-B, with the most recent common ancestors dating from 1945 and 1951, respectively. Seven new positively selected sites were identified in South African strains, 2 for RSV-A and 5 for RSV-B. CONCLUSION Positive selection drove both RSV-A and -B genotypes to evolve, resulting in replacement of all genotypes over the 15-year study period in South Africa.

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 Respiratory Syncytial Virus- Associated Acute Lower Respiratory Tract Infection Hospitalizations Among HIV-Infected and HIV-Uninfected South African Children, 2010-2011

BACKGROUND There are limited data on respiratory syncytial virus (RSV) infection among children in settings with a high prevalence of human immunodeficiency virus (HIV). We studied the epidemiology of RSV-associated acute lower respiratory tract infection (ALRTI) hospitalizations among HIV-infected and HIV-uninfected children in South Africa. METHODS Children aged <5 years admitted to sentinel surveillance hospitals with physician-diagnosed neonatal sepsis or ALRTI were enrolled. Nasopharyngeal aspirates were tested by multiplex real-time polymerase chain reaction assays for RSV and other viruses. Associations between possible risk factors and severe outcomes for RSV infection among HIV-infected and uninfected children were examined. The relative risk of hospitalization in HIV-infected and HIV-uninfected children was calculated in 1 site with population denominators. RESULTS Of 4489 participants, 4293 (96%) were tested for RSV, of whom 1157 (27%) tested positive. With adjustment for age, HIV-infected children had a 3-5-fold increased risk of hospitalization with RSV-associated ALRTI (2010 relative risk, 5.6; [95% confidence interval (CI), 4.5-6.4]; 2011 relative risk, 3.1 [95% CI, 2.6-3.6]). On multivariable analysis, HIV-infected children with RSV-associated ALRTI had higher odds of death (adjusted odds ratio. 31.1; 95% CI, 5.4-179.8) and hospitalization for >5 days (adjusted odds ratio, 4.0; 95% CI, 1.5-10.6) than HIV-uninfected children. CONCLUSION HIV-infected children have a higher risk of hospitalization with RSV-associated ALRTI and a poorer outcome than HIV-uninfected children. These children should be targeted for interventions aimed at preventing severe RSV disease.

Mortality amongst patients with influenza-associated severe acute respiratory illness, South Africa, 2009-2013.

Introduction 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. Methods 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. Results 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. Conclusion 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.

Epidemiology of Viral-associated Acute Lower Respiratory Tract Infection Among Children <5 Years of Age in a High HIV Prevalence Setting, South Africa, 2009–2012

Background: Data on the epidemiology of viral-associated acute lower respiratory tract infection (LRTI) from high HIV prevalence settings are limited. We aimed to describe LRTI hospitalizations among South African children aged <5 years. Methods: We prospectively enrolled hospitalized children with physician-diagnosed LRTI from 5 sites in 4 provinces from 2009 to 2012. Using polymerase chain reaction (PCR), nasopharyngeal aspirates were tested for 10 viruses and blood for pneumococcal DNA. Incidence was estimated at 1 site with available population denominators. Results: We enrolled 8723 children aged <5 years with LRTI, including 64% <12 months. The case-fatality ratio was 2% (150/8512). HIV prevalence among tested children was 12% (705/5964). The overall prevalence of respiratory viruses identified was 78% (6517/8393), including 37% rhinovirus, 26% respiratory syncytial virus (RSV), 7% influenza and 5% human metapneumovirus. Four percent (253/6612) tested positive for pneumococcus. The annual incidence of LRTI hospitalization ranged from 2530 to 3173/100,000 population and was highest in infants (8446–10532/100,000). LRTI incidence was 1.1 to 3.0-fold greater in HIV-infected than HIV-uninfected children. In multivariable analysis, compared to HIV-uninfected children, HIV-infected children were more likely to require supplemental-oxygen [odds ratio (OR): 1.3, 95% confidence interval (CI): 1.1–1.7)], be hospitalized >7 days (OR: 3.8, 95% CI: 2.8–5.0) and had a higher case-fatality ratio (OR: 4.2, 95% CI: 2.6–6.8). In multivariable analysis, HIV-infection (OR: 3.7, 95% CI: 2.2–6.1), pneumococcal coinfection (OR: 2.4, 95% CI: 1.1–5.6), mechanical ventilation (OR: 6.9, 95% CI: 2.7–17.6) and receipt of supplemental-oxygen (OR: 27.3, 95% CI: 13.2–55.9) were associated with death. Conclusions: HIV-infection was associated with an increased risk of LRTI hospitalization and death. A viral pathogen, commonly RSV, was identified in a high proportion of LRTI cases.

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.