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.
Human enterovirus 68 (EV-D68) is a historically rarely reported virus linked with respiratory disease. In the past 3 years, a large increase in respiratory disease associated with EV-D68 has been reported, with documented outbreaks in North America, Europe and Asia. In several outbreaks, genetic differences were identified among the circulating strains, indicating the presence of multiple clades. In this report, we analyse archived and novel EV-D68 strains from Africa and the USA, obtained from patients with respiratory illness. Phylogenetic analysis of all EV-D68 sequences indicates that, over the past two decades, multiple clades of the virus have emerged and spread rapidly worldwide. All clades appear to be currently circulating and contributing to respiratory disease.
The high cost of pneumococcal conjugate vaccine (PCV) and local epidemiological factors contributed to evaluating different PCV dosing-schedules. This study evaluated the immunogenicity of seven-valent PCV (PCV7) administered at 6-weeks; 14-weeks and 9-months of age.
250 healthy, HIV-unexposed infants were immunized with PCV7 concurrently with other childhood vaccines. Serotype-specific anti-capsular IgG concentrations were measured one-month following the 1st and 2nd PCV-doses, prior to and two-weeks following the 3rd dose. Opsonophagocytic killing assay (OPA) was measured for three serotypes following the 2nd and 3rd PCV7-doses. Immunogenicity of the current schedule was compared to a historical cohort of infants who received PCV7 at 6, 10 and 14 weeks of age.
The proportion of infants with serotype-specific antibody ≥0.35 µg/ml following the 2nd PCV7-dose ranged from 84% for 6B to ≥89% for other serotypes. Robust antibody responses were observed following the 3rd dose. The proportion of children with OPA ≥8 for serotypes 9V, 19F and 23F increased significantly following the 3rd PCV7-dose to 93.6%; 86.0% and 89.7% respectively. The quantitative antibody concentrations following the 2nd PCV7-dose were comparable to that after the 3rd -dose in the 6-10-14 week schedule. Geometric mean concentrations (GMCs) following the 3rd PCV7-dose were higher for all serotypes in this study compared to the historical cohort.
The studied PCV7 dosing schedule induced good immune responses, including higher GMCs following the 3rd-dose at 9-months compared to when given at 14-weeks of age. This may confer longer persistence of antibodies and duration of protection against pneumococcal disease.
There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing.
Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants ages 3–24 months receiving INH 10–20 mg/kg/day orally for Mycobacterium tuberculosis (TB) prophylaxis. INH pharmacokinetic parameters were characterized with a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) ≥ 3mg/L, and area under the curve (AUC0-24) ≥ 10.52 mg*hr/L.
In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg/kg/day, mean (±SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (±SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg*hr/L, respectively, and mean (±SD) half-life were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg/kg/day, 99% of infants ages 3–24 months have an INH Cmax ≥ 3 mg/L and 98% have an INH AUC0-24 ≥ 10.52 mg*hr/L.
INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values ≥ 3 mg/L and AUC0-24 values ≥ 10.52 mg*hr/L.
isoniazid; pharmacokinetics; dosing; infants; children
Multidrug resistant and extensively drug resistant tuberculosis (TB) have become major threats to control of tuberculosis globally. The rates of anti-TB drug resistance in Uganda are not known. We conducted a national drug resistance survey to investigate the levels and patterns of resistance to first and second line anti-TB drugs among new and previously treated sputum smear-positive TB cases.
Sputum samples were collected from a nationally representative sample of new and previously treated sputum smear-positive TB patients registered at TB diagnostic centers during December 2009 to February 2011 using a weighted cluster sampling method. Culture and drug susceptibility testing was performed at the national TB reference laboratory.
A total of 1537 patients (1397 new and 140 previously treated) were enrolled in the survey from 44 health facilities. HIV test result and complete drug susceptibility testing (DST) results were available for 1524 (96.8%) and 1325 (85.9%) patients, respectively. Of the 1209 isolates from new cases, resistance to any anti-TB drug was 10.3%, 5% were resistant to isoniazid, 1.9% to rifampicin, and 1.4% were multi drug resistant. Among the 116 isolates from previously treated cases, the prevalence of resistance was 25.9%, 23.3%, 12.1% and 12.1% respectively. Of the 1524 patients who had HIV testing 469 (30.7%) tested positive. There was no association between anti-TB drug resistance (including MDR) and HIV infection.
The prevalence of anti-TB drug resistance among new patients in Uganda is low relative to WHO estimates. The higher levels of MDR-TB (12.1%) and resistance to any drug (25.3%) among previously treated patients raises concerns about the quality of directly observed therapy (DOT) and adherence to treatment. This calls for strengthening existing TB control measures, especially DOT, routine DST among the previously treated TB patients or periodic drug resistance surveys, to prevent and monitor development and transmission of drug resistant TB.
Although seasonal variation in tuberculosis (TB) incidence has been described in many countries, it remains unknown in China.
A time series decomposition analysis (X-12-ARIMA) was performed to examine the seasonal variation in active TB cases nationwide from 2005 through 2012 in China. Seasonal amplitude was calculated for the evaluation of TB seasonal variation.
A total of 7.78 million active TB cases were reported over a period of 8 years. A spring peak (April) was observed with seasonal amplitude of 46.3%, compared with the winter trough (February). Most cases in provinces with subtropical and tropical monsoon climate showed lower amplitudes than those in temperate continental, plateau and mountain climate regions. The magnitude of seasonality varied inversely with annual average temperature, r (95% CI) = -0.71 (-0.79, -0.61). The seasonal amplitudes were 56.7, 60.5, 40.6, 46.4 and 50.9% for patients aged ≤14, 15–24, 25–44, 45–64, and ≥65 years, respectively. Students demonstrated greater seasonal amplitude than peasants, migrant workers and workers (115.3% vs. 43.5, 41.6 and 48.1%). Patients with pulmonary TB had lower amplitude compared to patients with pleural and other extra-pulmonary TB (EPTB) (45.9% vs. 52.0 and 56.3%). Relapse cases with sputum smear positive TB (SS+ TB) had significantly higher seasonal amplitude compared to new cases with sputum smear positive TB (52.2% vs. 41.6%).
TB is a seasonal disease in China. The peak and trough of TB transmission actually are in winter and in autumn respectively after factors of delay are removed. Higher amplitudes of TB seasonality are more likely to happen in temperate continental, plateau and mountain climate regions and regions with lower annual average temperature, and young person, students, patients with EPTB and relapse cases with SS+ TB are more likely to be affected by TB seasonality.
There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.
Heightened immunogenicity, measured one month after the primary series of pneumococcal conjugate vaccine (PCV), in African children was previously hypothesized to be due to increased rates of nasopharyngeal pneumococcal colonization during early infancy.
We analyzed the effect of selected vaccine-serotype (6B, 19F and 23F) nasopharyngeal colonization prior to the first PCV dose or when colonized for the first time prior to the second or third (2nd/3rd) PCV dose on serotype quantitative and qualitative antibody responses.
Colonization prior to receiving the first PCV was associated with lower geometric mean antibody concentrations (GMCs) one month after the third dose of PCV and six months later to the colonizing-serotype. Colonized infants also had lower geometric mean titers (GMTs) on opsonophagocytosis activity assay (OPA) and a lower proportion had titers ≥8 against the colonizing serotypes (19F and 23F) post vaccination. Colonization occurring only prior to the 2nd/3rd PCV dose was also associated with lower GMCs and OPA GMTs to the colonizing-serotype. The effect of colonization with serotypes 19F and 23F prior to PCV vaccination had a greater effect on a lower proportion of colonized infants having OPA titers ≥8 than the effect of colonization on the lower proportion with antibody ≥0.35 μg/ml.
Infant nasopharyngeal colonization at any stage before completing the primary series of PCV vaccination was associated with inferior quantitative and qualitative antibody responses to the colonizing-serotype.
Streptococcus pneumoniae; pneumococcal conjugate vaccine; HIV; immunogenicity; colonization; hypo-responsiveness
Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season.
Healthy infants aged 5–10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI.
Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P (20 [1.4%] in placebo) and P (13 [0.9%] in placebo). Vaccine efficacy against P was 59.1% (95% CI: 32.8%; 75.3%), P was 70.9% (95% CI: 37.5%; 87.0%) and P was 55.2% (95% CI: -6.5%; 81.3%)
Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™.
Trial registration number
The Expanded Programme on Immunisation (EPI) is one of the most powerful and cost-effective public health programmes to improve child survival. We assessed challenges and enablers for the programme in South Africa, as we approach the 2015 deadline for the Millennium Development Goals.
Between September 2009 and September 2010 we requested national and provincial EPI managers in South Africa to identify key challenges facing EPI, and to propose appropriate solutions. We collated their responses and searched for systematic reviews on the effectiveness of the proposed solutions; in the Health Systems Evidence, Cochrane Library, and PubMed electronic databases. We screened the search outputs, selected systematic reviews, extracted data, and assessed the quality of included reviews (using AMSTAR) and the quality of the evidence (using GRADE) in duplicate; resolving disagreements by discussion and consensus.
Challenges identified by EPI managers were linked to healthcare workers (insufficient knowledge of vaccines and immunisation), the public (anti-immunisation rumours and reluctance from parents), and health system (insufficient financial and human resources). Strategies proposed by managers to overcome the challenges include training, supervision, and audit and feedback; strengthening advocacy and social mobilisation; and sustainable EPI funding schemes, respectively. The findings from reliable systematic reviews indicate that interactive educational meetings, audit and feedback, and supportive supervision improve healthcare worker performance. Structured and interactive communication tools probably increase parents’ understanding of immunisation; and reminders and recall, use of community health workers, conditional cash transfers, and mass media interventions probably increase immunisation coverage. Finally, a national social health insurance scheme is a potential EPI financing mechanism; however, given the absence of high-quality evidence of effects, its implementation should be pilot-tested and the impacts and costs rigorously monitored.
In line with the Millennium Development Goals, we have to ensure that our children’s right to health, development and survival is respected, protected and promoted. EPI is central to this vision. We found numerous promising strategies for improving EPI performance in South Africa. However, their implementation would need to be tailored to local circumstances and accompanied by high-quality monitoring and evaluation. The strength of our approach comes from having a strong framework for interventions before looking for systematic reviews. Without a framework, we would have been driven by what reviews have been done and what is easily researchable; rather than the values and preferences of key immunisation stakeholders.
Few studies have examined outcomes for children treated for multidrug-resistant tuberculosis (MDR-TB), including those receiving concomitant treatment for MDR-TB and HIV co-infection. In Lesotho, where the adult HIV seroprevalence is estimated to be 24%, we sought to measure outcomes and adverse events in a cohort of children treated for MDR-TB using a community-based treatment delivery model.
We reviewed retrospectively the clinical charts of children ≤15 years of age treated for culture-confirmed or suspected MDR-TB between July 2007 and January 2011.
Nineteen children, ages two to 15, received treatment. At baseline, 74% of patients were co-infected with HIV, 63% were malnourished, 84% had severe radiographic findings, and 21% had extrapulmonary disease. Five (26%) children had culture-confirmed MDR-TB, ten (53%) did not have culture results available, and four (21%) subsequently had results indicating drug-susceptible TB. All children with HIV co-infection who were not already on antiretroviral therapy (ART) were initiated on ART a median of two weeks after the start of the MDR-TB regimen. Among the 17 patients with final outcomes, 15 (88%) patients were cured or completed treatment, two (12%) patients died, and none defaulted or were lost to follow-up. The majority of patients (95%) experienced adverse events; only two required permanent discontinuation of the offending agent, and only one required suspension of MDR-TB treatment for more than one week.
Pediatric MDR-TB and MDR-TB/HIV co-infection can be successfully treated using a combination of social support, close monitoring by community health workers and clinicians, and inpatient care when needed. In this cohort, adverse events were well tolerated and treatment outcomes were comparable to those reported in children with drug-susceptible TB and no HIV infection.
The Pneumonia Etiology Research for Child Health (PERCH) project is a 7-country, standardized, comprehensive evaluation of the etiologic agents causing severe pneumonia in children from developing countries. During previous etiology studies, between one-quarter and one-third of patients failed to yield an obvious etiology; PERCH will employ and evaluate previously unavailable innovative, more sensitive diagnostic techniques. Innovative and rigorous epidemiologic and analytic methods will be used to establish the causal association between presence of potential pathogens and pneumonia. By strategic selection of study sites that are broadly representative of regions with the greatest burden of childhood pneumonia, PERCH aims to provide data that reflect the epidemiologic situation in developing countries in 2015, using pneumococcal and Haemophilus influenzae type b vaccines. PERCH will also address differences in host, environmental, and/or geographic factors that might determine pneumonia etiology and, by preserving specimens, will generate a resource for future research and pathogen discovery.
Pneumonia is the leading cause of childhood death in Bangladesh. We conducted a longitudinal study to estimate the incidence of virus-associated pneumonia in children aged <2 years in a low-income urban community in Dhaka, Bangladesh.
We followed a cohort of children for two years. We collected nasal washes when children presented with respiratory symptoms. Study physicians diagnosed children with cough and age-specific tachypnea and positive lung findings as pneumonia case-patients. We tested respiratory samples for respiratory syncytial virus (RSV), rhinoviruses, human metapneumovirus (HMPV), influenza viruses, human parainfluenza viruses (HPIV 1, 2, 3), and adenoviruses using real-time reverse transcription polymerase chain reaction assays.
Between April 2009–March 2011, we followed 515 children for 730 child-years. We identified a total of 378 pneumonia episodes, 77% of the episodes were associated with a respiratory viral pathogen. The overall incidence of pneumonia associated with a respiratory virus infection was 40/100 child-years. The annual incidence of pneumonia/100 child-years associated with a specific respiratory virus in children aged <2years was 12.5 for RSV, 6 for rhinoviruses, 6 for HMPV, 4 for influenza viruses, 3 for HPIV and 2 for adenoviruses.
Young children in Dhaka are at high risk of childhood pneumonia and the majority of these episodes are associated with viral pathogens. Developing effective low-cost strategies for prevention are a high priority.
A 9-valent pneumococcal conjugate vaccine (PCV-9), given in a 3-dose schedule, protected Gambian children against pneumococcal disease and reduced nasopharyngeal carriage of pneumococci of vaccine serotypes. We have studied the effect of a booster or delayed primary dose of 7-valent conjugate vaccine (PCV-7) on antibody and nasopharyngeal carriage of pneumococci 3–4 years after primary vaccination.
We recruited a subsample of children who had received 3 doses of either PCV-9 or placebo (controls) into this follow-up study. Pre- and post- PCV-7 pneumococcal antibody concentrations to the 9 serotypes in PCV-9 and nasopharyngeal carriage of pneumococci were determined before and at intervals up to 18 months post-PCV-7. We enrolled 282 children at a median age of 45 months (range, 38–52 months); 138 had received 3 doses of PCV-9 in infancy and 144 were controls. Before receiving PCV-7, a high proportion of children had antibody concentrations >0.35 µg/mL to most of the serotypes in PCV-9 (average of 75% in the PCV-9 and 66% in the control group respectively). The geometric mean antibody concentrations in the vaccinated group were significantly higher compared to controls for serotypes 6B, 14, and 23F. Antibody concentrations were significantly increased to serotypes in the PCV-7 vaccine both 6–8 weeks and 16–18 months after PCV-7. Antibodies to serotypes 6B, 9V and 23F were higher in the PCV-9 group than in the control group 6–8 weeks after PCV-7, but only the 6B difference was sustained at 16–18 months. There was no significant difference in nasopharyngeal carriage between the two groups.
Pneumococcal antibody concentrations in Gambian children were high 34–48 months after a 3-dose primary infant vaccination series of PCV-9 for serotypes other than serotypes 1 and 18C, and were significantly higher than in control children for 3 of the 9 serotypes. Antibody concentrations increased after PCV-7 and remained raised for at least 18 months.
There is an emergence of drug-resistant-TB (DR-TB) in settings affected by HIV and tuberculosis (TB).
We investigated the prevalence of DR-TB in P1041, a multi-centred, randomized, double-blind trial which compared administration of INH to placebo, in HIV-exposed-uninfected and HIV-infected African infants in the absence of any documented TB exposure.
The prevalence of MDR-TB was 22.2% (95% CI: 8.5–45.8%) and INH monoresistance 5.6% (95% CI 0.1–27.6%) amongst culture-confirmed cases with all MDR-TB occurring in a single site. There was no association between INH treatment or placebo group, or between HIV infection status, and DR-TB prevalence.
There was a high prevalence of DR-TB amongst HIV-exposed and infected children. Surveillance of DR-TB amongst children in high-burden TB/HIV settings should be routine.
Streptococcus pneumoniae is the leading bacterial opportunistic infection in HIV-infected individuals. Anti-retroviral treatment (ART) of HIV-infected individuals reduces their risk of invasive pneumococcal disease (IPD), however, it remains 20- to 40-fold greater compared with age-matched general population. This review summarizes the available published data on the immunogenicity, safety and efficacy of pneumococcal polysaccharide-protein conjugate vaccines (PCV) in HIV-infected children and adults.
Several studies have demonstrated that PCV are safe in the HIV-infected persons. Although PCV are immunogenic in HIV-infected infants, the antibodies produced are functionally impaired, there is possibly a lack or loss of anamnestic responses and immunity declines in later life However, quantitative and qualitative antibody responses to PCV in HIV-infected infants are enhanced when vaccination occurs whilst on ART, as well as if vaccination occurs when the CD4+ cell percentage is ≥ 25% and if the nadir CD4+ is >15%. Although the efficacy of PCV was lower, the vaccine preventable burden of hospitalization for IPD and clinical pneumonia were 18-fold and 9-fold greater, respectively, in HIV-infected children compared with –uninfected children.
In HIV-infected adults, PCV vaccination induces more durable and functional antibody responses in individuals on ART at the time of vaccination than in ART-naive adults, independently of baseline CD4+ cell count, although there does not appear to be much benefit from a second-dose of PCV. PCV has also been shown to reduce the risk of recurrent IPD by 74% in HIV-infected adults not on ART, albeit, also with subsequent decline in immunity and protection.
Streptococcus pneumoniae; HIV; immunogenicity; pneumococcal conjugate vaccine; pneumococcal disease
Pneumonia is a leading cause of death in children worldwide. A simple clinical score predicting the probability of death in a young child with lower respiratory tract infection (LRTI) could aid clinicians in case management and provide a standardized severity measure during epidemiologic studies.
We analyzed 4,148 LRTI hospitalizations in children <24 months enrolled in a pneumococcal conjugate vaccine trial in South Africa from 1998–2001, to develop the Respiratory Index of Severity in Children (RISC). Using clinical data at admission, a multivariable logistic regression model for mortality was developed and statistically evaluated using bootstrap resampling techniques. Points were assigned to risk factors based on their coefficients in the multivariable model. A child's RISC score is the sum of points for each risk factor present. Separate models were developed for HIV-infected and non-infected children.
Significant risk factors for HIV-infected and non-infected children included low oxygen saturation, chest indrawing, wheezing, and refusal to feed. The models also included age and HIV clinical classification (for HIV-infected children) or weight-for-age (for non-infected children). RISC scores ranged up to 7 points for HIV-infected or 6 points for non-infected children and correlated with probability of death (0–47%, HIV-infected; 0–14%, non-infected). Final models showed good discrimination (area under the ROC curve) and calibration (goodness-of-fit).
The RISC score incorporates a simple set of risk factors that accurately discriminate between young children based on their risk of death from LRTI, and may provide an objective means to quantify severity based on the risk of mortality.
Background. Although essential to guide control measures, published estimates of influenza-related seasonal mortality for low- and middle-income countries are few. We aimed to compare influenza-related mortality among individuals aged ⩾65 years in South Africa and the United States.
Methods. We estimated influenza-related excess mortality due to all causes, pneumonia and influenza, and other influenza-associated diagnoses from monthly age-specific mortality data for 1998–2005 using a Serfling regression model. We controlled for between-country differences in population age structure and nondemographic factors (baseline mortality and coding practices) by generating age-standardized estimates and by estimating the percentage excess mortality attributable to influenza.
Results. Age-standardized excess mortality rates were higher in South Africa than in the United States: 545 versus 133 deaths per 100,000 population for all causes (P < .001) and 63 vs 21 deaths per 100,000 population for pneumonia and influenza (P=.03). Standardization for nondemographic factors decreased but did not eliminate between-country differences; for example, the mean percentage of winter deaths attributable to influenza was 16% in South Africa and 6% in the United States (P < .001). For all respiratory causes, cerebrovascular disease, and diabetes, age-standardized excess death rates were 4—8-fold greater in South Africa than in the United States, and the percentage increase in winter deaths attributable to influenza was 2—4-fold higher.
Conclusions. These data suggest that the impact of seasonal influenza on mortality among elderly individuals may be substantially higher in an African setting, compared with in the United States, and highlight the potential for influenza vaccination programs to decrease mortality.
Live vaccines have distinct safety profiles, potentially causing systemic reactions one to 2 weeks after administration. In the province of Ontario, Canada, live MMR vaccine is currently recommended at age 12 months and 18 months.
Using the self-controlled case series design we examined 271,495 12 month vaccinations and 184,312 18 month vaccinations to examine the relative incidence of the composite endpoint of emergency room visits or hospital admissions in consecutive one day intervals following vaccination. These were compared to a control period 20 to 28 days later. In a post-hoc analysis we examined the reasons for emergency room visits and the average acuity score at presentation for children during the at-risk period following the 12 month vaccine.
Four to 12 days post 12 month vaccination, children had a 1.33 (1.29–1.38) increased relative incidence of the combined endpoint compared to the control period, or at least one event during the risk interval for every 168 children vaccinated. Ten to 12 days post 18 month vaccination, the relative incidence was 1.25 (95%, 1.17–1.33) which represented at least one excess event for every 730 children vaccinated. The primary reason for increased events was statistically significant elevations in emergency room visits following all vaccinations. There were non-significant increases in hospital admissions. There were an additional 20 febrile seizures for every 100,000 vaccinated at 12 months.
There are significantly elevated risks of primarily emergency room visits approximately one to two weeks following 12 and 18 month vaccination. Future studies should examine whether these events could be predicted or prevented.
We describe pregnant womens' access to PMTCT and HAART services and associated birth outcomes in South Africa.
Women recuperating in postnatal wards of a referral hospital participated in an evaluation during February–May 2010 during which their maternity records were examined to describe their access to VCT, CD4 Counts, dual ART or HAART during pregnancy.
Of the 1609 women who participated in this evaluation, 39% (95%CI36.7–41.5%) tested HIV-positive during their pregnancy. Of the HIV-positive women 2.9% did not have a CD4 count done and an additional 31.3% did not receive their CD4 results. The majority (96.8%) of the HIV-positive women commenced dual ART at their first antenatal visit independent of their CD4 result. During February–May 2010, 48.0% of the women who had a CD4 result were eligible for HAART (CD4<200 cells/mm3) and 29.1% of these initiated HAART during pregnancy. Under the current South African PMTCT guidelines 71.1% (95%CI66.4–75.4%) of HIV positive pregnant women could be eligible for HAART (CD4<350 cells/mm3). There were significantly more preterm births among HIV-positive women (p = 0.01) and women who received HAART were no more at risk of preterm deliveries (AOR 0.73;95%CI0.39–1.36;p = 0.2) as compared to women who received dual ART. Nine (2.4%; 95%CI1.1–4.5%) HIV exposed infants were confirmed HIV infected at birth. The in-utero transmission rate was highest among women who required HAART but did not initiate treatment (8.5%) compared to 2.7% and 0.4% among women who received HAART and women who were not eligible for HAART and received PMTCT prophylaxis respectively.
In this urban South African community the antenatal HIV prevalence remains high (39%) and timeous access to CD4 results during pregnancy is limited. Under the current South African guidelines, and assuming that access to CD4 results has improved, more than 70% of HIV-positive pregnant women in this community would be requiring HAART.
Highly active antiretroviral treatment (HAART) programs have been associated with declines in the burden of invasive pneumococcal disease (IPD) in industrialized countries. The aim of this study was to evaluate trends in IPD hospitalizations in HIV-infected adults in Soweto, South Africa, associated with up-scaling of the HAART program from 2003 to 2008.
Laboratory-confirmed IPD cases were identified from 2003 through 2008 through an existing surveillance program. The period 2003-04 was designated as the early-HAART era, 2005–06 as the intermediate-HAART era and 2007–08 as the established-HAART era. The incidence of IPD was compared between the early-HAART and established-HAART eras in HIV-infected and–uninfected individuals.
A total of 2,567 IPD cases among individuals older than 18 years were reported from 2003 through 2008. Overall incidence of IPD (per 100,000) did not change during the study period in HIV-infected adults (207.4 cases in the early-HAART and 214.0 cases in the established-HAART era; p = 0.55). IPD incidence, actually increased 1.16-fold (95% CI: 1.01; 1.62) in HIV-infected females between the early-and established-HAART eras (212.1 cases and 246.2 cases, respectively; p = 0.03). The incidence of IPD remained unchanged in HIV-uninfected adults across the three time periods.
Despite a stable prevalence of HIV and the increased roll-out of HAART for treatment of AIDS patients in our setting, the burden of IPD has not decreased among HIV-infected adults. The study indicates a need for ongoing monitoring of disease and HAART program effectiveness to reduce opportunistic infections in African adults with HIV/AIDS, as well as the need to consider alternate strategies including pneumococcal conjugate vaccine immunization for the prevention of IPD in HIV-infected adults.
As HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa.
HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fisher's exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings.
417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50th centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression.
A combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere.
QuantiFERON-TB Gold In Tube (QFT-GIT) is a tool for detecting M. tuberculosis infection. However, interpretation and utility of serial QFT-GIT testing of pediatric tuberculosis (TB) contacts is not well understood. We compared TB prevalence between baseline and 6 months follow-up using QFT-GIT and tuberculin skin testing (TST) in children who were household contacts of adults with pulmonary TB in South Africa, and explored factors associated with QFT-GIT conversions and reversions.
Prospective study with six month longitudinal follow-up.
Among 270 enrolled pediatric contacts, 196 (73%) underwent 6-month follow-up testing. The 6-month prevalence estimate of MTB infection in pediatric contacts increased significantly from a baseline of 29% (79/270, 95%CI [24–35]) to 38% (103/270, 95% CI [32–44], p<0.001) using QFT-GIT; prevalence increased from a baseline of 28% (71/254, 95%CI [23–34]) to 33% (88/263, 95%CI [21–32], p = 0.002) using TST. Prevalence estimates were influenced by thresholds for positivity for TST, but not for QFT-GIT. Among 134 children with a negative or indeterminate baseline QFT-GIT, 24 (18%) converted to positive at follow-up; conversion rates did not differ significantly when using more stringent thresholds to define QFT-GIT conversion. Older age >10 years (AOR 8.9 95%CI [1.1–72]) and baseline TST positivity ≥5 mm (AOR 5.2 95%CI [1.2–23]) were associated with QFT-GIT conversion. Among 62 children with a positive baseline QFT-GIT, 9 (15%) reverted to negative; female gender (AOR 18.5 95%CI [1.1–321]; p = 0.04] was associated with reversion, while children with baseline positive TST were less likely to have QFT-GIT reversion (AOR 0.01 95%CI [0.001–0.24]).
Among pediatric contacts of adult household TB cases in South Africa, prevalence estimates of TB infection increased significantly from baseline to 6 months. Conversions and reversions occurred among pediatric TB contacts using QFT-GIT, but QFT-GIT conversion rates were less influenced by thresholds used for conversions than were TST conversion rates.
Although otorrhea occurs commonly in HIV-infected infants, there are few data. We compared the incidence of otorrhea in infants receiving early vs deferred ART in the Children with HIV Early Antiretroviral (CHER) trial. Infants aged 6 to 12 weeks of age with confirmed HIV infection and a CD4 percentage greater than or equal to 25% were randomized to early or deferred ART at two sites in South Africa. Medical records from one study site were reviewed for otorrhea.
Data were reviewed from the start of the trial in July 2005 until 20 June 2007, when the Data Safety Monitoring Board recommended that randomization to the deferred arm should stop and that all infants in this arm be reviewed for commencing antiretroviral therapy. Infants entered the study at a median of 7.4 weeks of age. Eleven of 38 (29%) on deferred therapy and 7 of 75 (9%) in the early-therapy group developed otorrhea (risk ratio 3.1, 95% confidence interval (CI) 1.31-7.36; p = 0.01).
Early initiation of antiretroviral therapy is associated with significantly less otorrhea than when a deferred strategy is followed.
All fully sequenced strains of Streptococcus pneumoniae possess a version of the blp locus, which is responsible for bacteriocin production and immunity. Activation of the blp locus is stimulated by accumulation of the peptide pheromone, BlpC, following its secretion by the ABC transporter, BlpA. The blp locus is characterized by significant diversity in blpC type and in the region of the locus containing putative bacteriocin and immunity genes. In addition, the blpA gene can represent a single large open reading frame or be divided into several smaller fragments due to the presence of frameshift mutations. In this study, we use a collection of strains with blp-dependent inhibition and immunity to define the genetic changes that bring about phenotypic differences in bacteriocin production or immunity. We demonstrate that alterations in blpA, blpC, and bacteriocin/immunity content likely play an important role in competitive interactions between pneumococcal strains. Importantly, strains with a highly conserved frameshift mutation in blpA are unable to secrete bacteriocins or BlpC, but retain the ability to respond to exogenous peptide pheromone produced by cocolonizing strains, stimulating blp-mediated immunity. These “cheater” strains can only coexist with bacteriocin-producing strains that secrete their cognate BlpC and share the same immunity proteins. The variable outcome of these interactions helps to explain the heterogeneity of the blp pheromone, bacteriocin, and immunity protein content.
Streptococcus pneumoniae resides in a polymicrobial environment and competes for limited resources by the elaboration of small antimicrobial peptides called bacteriocins. A conserved cluster of genes in the S. pneumoniae genome is involved in the production of bacteriocins and their associated protective immunity proteins through secretion of a signaling pheromone. In this study, we show that a significant number of strains have lost the ability to secrete bacteriocins and signaling pheromones due to a specific mutation in a dedicated transporter protein. Because the regulatory and immunity portion of the locus is retained, these “cheater” strains can survive in the face of invasion from a bacteriocin-producing strain without the cost of bacteriocin secretion. The outcome of such interactions depends on each strain’s repertoire of pheromone, immunity protein, and bacteriocin genes, such that intrastrain competition drives the diversity in bacteriocin, immunity protein, and pheromone content.