Michelle J. Groome

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.

Chlorhexidine maternal-vaginal and neonate body wipes in sepsis and vertical transmission of pathogenic bacteria in South Africa: a randomised, controlled trial

BACKGROUND About 500,000 sepsis-related deaths per year arise in the first 3 days of life. On the basis of results from non-randomised studies, use of vaginal chlorhexidine wipes during labour has been proposed as an intervention for the prevention of early-onset neonatal sepsis in developing countries. We therefore assessed the efficacy of chlorhexidine in early-onset neonatal sepsis and vertical transmission of group B streptococcus. METHODS In a trial in Soweto, South Africa, 8011 women (aged 12-51 years) were randomly assigned in a 1:1 ratio to chlorhexidine vaginal wipes or external genitalia water wipes during active labour, and their 8129 newborn babies were assigned to full-body (intervention group) or foot (control group) washes with chlorhexidine at birth, respectively. In a subset of mothers (n=5144), we gathered maternal lower vaginal swabs and neonatal skin swabs after delivery to assess colonisation with potentially pathogenic bacteria. Primary outcomes were neonatal sepsis in the first 3 days of life and vertical transmission of group B streptococcus. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00136370. FINDINGS Rates of neonatal sepsis did not differ between the groups (chlorhexidine 141 [3%] of 4072 vs control 148 [4%] of 4057; p=0.6518). Rates of colonisation with group B streptococcus in newborn babies born to mothers in the chlorhexidine (217 [54%] of 401) and control groups (234 [55%] of 429] did not differ (efficacy -0.05%, 95% CI -9.5 to 7.9). INTERPRETATION Because chlorhexidine intravaginal and neonatal wipes did not prevent neonatal sepsis or the vertical acquisition of potentially pathogenic bacteria among neonates, we need other interventions to reduce childhood mortality. FUNDING US Agency for International Development, National Vaccine Program Office and Centers for Disease Controls Antimicrobial Resistance Working Group, and Bill & Melinda Gates Foundation.

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.

Impact of rotavirus vaccine on childhood diarrheal hospitalization after introduction into the South African public immunization program.

Background: Oral rotavirus vaccine was introduced into the South African routine immunization program in August 2009 administered at 6 and 14 weeks with no catch-up. We described the change in rotavirus-associated diarrheal hospitalizations among children <5 years at 3 sentinel sites from 2009 through 2011. Methods: During 2009 through 2011, we compared the proportion of enrolled children aged <5 years hospitalized with acute gastroenteritis and testing rotavirus positive. We used hospital data to determine the change in diarrhea hospitalizations and estimated total numbers of rotavirus hospitalizations by adjusting for nonenrolled patients. Stool samples were tested for rotavirus using enzyme immunoassay. Results: In 2009 (May–December), 46% (404/883) of samples among children <5 years tested rotavirus positive, decreasing to 33% (192/580) (P < 0.001) in 2010 and 29% (113/396) (P < 0.001) in 2011. Compared with May–December 2009, total diarrhea hospitalizations among children aged <5 years was one-third lower in May–December of 2010 and 2011. Among infants, adjusted rotavirus hospitalizations were 61% (n = 267) and 69% (n = 214) lower, respectively, in 2010 and 2011 when compared with 2009 (n = 689), and 45 and 50 percentage points greater than the reduction in rotavirus-negative cases. Among children <5 years, rotavirus hospitalizations were 54% and 58% lower in 2010 and 2011, compared with 2009 (40 and 44 percentage points greater than reduction in rotavirus-negative cases). Rotavirus reductions occurred in rural and urban settings. Conclusion: Using published estimates of rotavirus hospitalization burden, we estimate that at least 13,000 to 20,000 hospitalizations in children <2 years were prevented in the 2 years after rotavirus vaccine introduction.

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.

Maternal HIV Infection and Vertical Transmission of Pathogenic Bacteria

BACKGROUND: HIV-exposed newborns may be at higher risk of sepsis because of immune system aberrations, impaired maternal antibody transfer and altered exposure to pathogenic bacteria. METHODS: We performed a secondary analysis of a study (clinicaltrials.gov, number NCT00136370) conducted between April 2004 and October 2007 in South Africa. We used propensity score matching to evaluate the association between maternal HIV infection and (1) vaginal colonization with bacterial pathogens; (2) vertical transmission of pathogens to the newborn; and (3) sepsis within 3 days of birth (EOS) or between 4–28 days of life (LOS). RESULTS: Colonization with group B Streptococcus (17% vs 23%, P = .0002), Escherichia coli (47% vs 45%, P = .374), and Klebsiella pneumoniae (7% vs 10%, P = .008) differed modestly between HIV-infected and uninfected women, as did vertical transmission rates. Maternal HIV infection was not associated with increased risk of neonatal EOS or LOS, although culture-confirmed EOS was >3 times higher among HIV-exposed infants (P = .05). When compared with HIV-unexposed, neonates, HIV-exposed, uninfected neonates (HEU) had a lower risk of EOS (20.6 vs 33.7 per 1000 births; P = .046) and similar rate of LOS (5.8 vs 4.1; P = .563). HIV-infected newborns had a higher risk than HEU of EOS (134 vs 21.5; P < .0001) and LOS (26.8 vs 5.6; P = .042). CONCLUSIONS: Maternal HIV infection was not associated with increased risk of maternal bacterial colonization, vertical transmission, EOS, or LOS. HIV-infected neonates, however, were at increased risk of EOS and LOS.

Increased risk for group B Streptococcus sepsis in young infants exposed to HIV Soweto South Africa 2004-2008(1).

Vaccination of pregnant women could prevent 2,105 invasive GBS cases and 278 deaths among infants annually.

Risk factors for neonatal sepsis and perinatal death among infants enrolled in the prevention of perinatal sepsis trial, Soweto, South Africa.

Background: Factors associated with neonatal sepsis, an important cause of child mortality, are poorly described in Africa. We characterized factors associated with early-onset (days 0–2 of life) and late-onset (days 3–28) sepsis and perinatal death among infants enrolled in the Prevention of Perinatal Sepsis Trial (NCT00136370 at ClinicalTrials.gov), Soweto, South Africa. Methods: Secondary analysis of 8011 enrolled mothers and their neonates. Prenatal and labor records were abstracted and neonatal wards were monitored for hospitalized Prevention of Perinatal Sepsis–enrolled neonates. Endpoint definitions required clinical and laboratory signs. All univariate factors associated with endpoints at P < 0.15 were evaluated using multivariable logistic regression. Results: About 10.5% (837/8011) of women received intrapartum antibiotic prophylaxis; 3.8% of enrolled versus 15% of hospital births were preterm. Among 8129 infants, 289 had early-onset sepsis, 34 had late-onset sepsis, 49 had culture-confirmed neonatal sepsis and 71 died in the perinatal period. Factors associated with early-onset sepsis included preterm delivery [adjusted relative risk (aRR) = 2.6; 95% confidence interval (CI): 1.4–4.8]; low birth weight (<1500 g: aRR = 6.5, 95% CI: 2.4–17.3); meconium-stained amniotic fluid (MSAF) (aRR = 2.8, 95% CI: 2.2–3.7) and first birth (aRR = 1.8; 95% CI: 1.4–2.3). Preterm, low birth weight, MSAF and first birth were similarly associated with perinatal death and culture-confirmed sepsis. MSAF (aRR = 2.4, 95% CI: 1.1–5.0) was associated with late-onset sepsis. Conclusions: Preterm and low birth weight were important sepsis risk factors. MSAF and first birth were also associated with sepsis and death, warranting further exploration. Intrapartum antibiotic prophylaxis did not protect against all-cause sepsis or death, underscoring the need for alternate prevention strategies.