Sibongile Walaza

Respiratory Viral Coinfections Identified by a 10-Plex Real-Time Reverse-Transcription Polymerase Chain Reaction Assay in Patients Hospitalized With Severe Acute Respiratory Illness—South Africa, 2009–2010

BACKGROUND Data about respiratory coinfections with 2009 pandemic influenza A virus subtype H1N1 during the 2009-2010 influenza pandemic in Africa are limited. We used an existing surveillance program for severe acute respiratory illness to evaluate a new multiplex real-time polymerase chain reaction assay and investigate the role of influenza virus and other respiratory viruses in pneumonia hospitalizations during and after the influenza pandemic in South Africa. METHODS The multiplex assay was developed to detect 10 respiratory viruses, including influenza A and B viruses, parainfluenza virus types 1-3, respiratory syncytial virus (RSV), enterovirus, human metapneumovirus (hMPV), adenovirus (AdV), and rhinovirus (RV), followed by influenza virus subtyping. Nasopharyngeal and oropharyngeal specimens were collected from patients hospitalized with pneumonia at 6 hospitals during 2009-2010. RESULTS Validation against external quality controls confirmed the high sensitivity (91%) and specificity (100%) and user-friendliness, compared with other PCR technologies. Of 8173 patients, 40% had single-virus infections, 17% had coinfections, and 43% remained negative. The most common viruses were RV (25%), RSV (14%), AdV (13%), and influenza A virus (5%). Influenza virus, RSV, PIV type 3, and hMPV showed seasonal patterns. CONCLUSION The data provide a better understanding of the viral etiology of hospitalized cases of pneumonia and demonstrate the usefulness of this multiplex assay in respiratory disease surveillance in South Africa.

Effectiveness of monovalent human rotavirus vaccine against admission to hospital for acute rotavirus diarrhoea in South African children: a case-control study

BACKGROUND The effectiveness of the rotavirus vaccine under conditions of routine use in an African setting with a high prevalence of HIV infection needs to be established. We assessed the vaccine effectiveness of monovalent human rotavirus vaccine in preventing admission to hospital for acute rotavirus diarrhoea, after its introduction at age 6 and 14 weeks into South Africas national immunisation programme. METHODS This case-control study was done at seven hospitals in South Africa between April 19, 2010, and Oct 31, 2012. The hospitals were located in a range of urban, peri-urban, and rural settings, with varying rates of population HIV infection. Cases were children aged from 18 weeks to 23 months who were age-eligible to have received at least one dose of the human rotavirus vaccine (ie, those born after June 14, 2009) admitted to hospital with laboratory-confirmed acute rotavirus diarrhoea, and the primary control group was children admitted to hospital with diarrhoea testing negative for rotavirus. A second control group comprised children admitted to a subset of three of the seven hospitals with respiratory illness. The primary endpoint was adjusted vaccine effectiveness (1 - adjusted odds ratio × 100%) in children aged from 18 weeks to 23 months and was calculated by unconditional logistic regression. This study is registered on the South African National Clinical Trial Register, number DOH-27-0512-3247. FINDINGS Of 540 rotavirus-positive cases, 278 children (52%) received two doses, 126 (23%) one dose, and 136 (25%) no doses of human rotavirus vaccine, compared with 1434 rotavirus-negative controls of whom 856 (60%) received two doses, 334 (23%) one dose, and 244 (17%) no doses. Adjusted vaccine effectiveness using rotavirus-negative controls was 57% (95% CI 40-68) for two doses and 40% (16-57) for one dose; estimates were similar when respiratory controls were used as the control group. Adjusted vaccine effectiveness for two doses was similar between age groups 18 weeks-11 months (54%, 95% CI 32-68) and 12-23 months (61%, 35-77), and was similar in HIV-exposed-uninfected (64%, 95% CI 34-80) and HIV-unexposed-uninfected children (54%, 31-69). INTERPRETATION Human rotavirus vaccine provided sustained protection against admission to hospital for acute rotavirus diarrhoea during the first and second years of life. This finding is encouraging and establishes the public health value of rotavirus vaccine in an African setting, especially as rotavirus vaccines are introduced into an increasing number of African countries. FUNDING GAVI Alliance (with support from PATH).

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.

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.

HIV and Influenza Virus Infections Are Associated With Increased Blood Pneumococcal Load: A Prospective, Hospital-Based Observational Study in South Africa, 2009–2011

BACKGROUND Increased pneumococcal loads are associated with severe outcomes. We determined the prevalence of pneumococcal DNA in blood specimens from patients hospitalized with acute lower respiratory tract infection and identified factors associated with invasive pneumococcal pneumonia, bacterial loads, and death. METHODS A total of 8523 patients were enrolled as part of prospective hospital-based surveillance. Blood was collected for quantitative pneumococcal (lytA) detection, and nasopharyngeal specimens were collected for detection of influenza virus and other respiratory viruses by real-time polymerase chain reaction. RESULTS Of 6396 cases (75%) with lytA results, 422 (7%) were positive for pneumococcal DNA. The prevalences of human immunodeficiency virus (HIV) and influenza virus were 51% (2965/5855) and 8% (485/6358), respectively. On multivariable analysis, HIV infection (adjusted odds ratio [aOR], 2.4; 95% confidence interval [CI], 1.6-3.6), influenza virus coinfection (aOR, 1.4; 95% CI, 1.2-2.1), oxygen therapy during admission (aOR, 1.6; 95% CI, 1.1-2.3) and in-hospital death (aOR, 2.1; 95% CI, 1.1-4.0) were significantly associated with increased pneumococcal load. Among lytA-positive patients, after adjustment for length of hospitalization, duration of symptoms, and oxygen therapy during admission, pneumococcal loads ≥10,000 DNA copies/mL (aOR, 3.6; 95% CI, 1.8-7.2) were associated with increased risk of death. CONCLUSIONS HIV and influenza virus infections were associated with elevated pneumococcal loads, which, in turn, were associated with increased risk of death.

Epidemiology of severe acute respiratory illness (SARI) among adults and children aged ≥5 years in a high HIV-prevalence setting, 2009-2012.

Objective 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. Methods 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. Findings 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). Conclusion 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.