Seasonality and within-subject clustering of rotavirus infections in an eight-site birth cohort study.

Improving understanding of the pathogen-specific seasonality of enteric infections is critical to informing policy on the timing of preventive measures and to forecast trends in the burden of diarrhoeal disease. Data obtained from active surveillance of cohorts can capture the underlying infection status as transmission occurs in the community. The purpose of this study was to characterise rotavirus seasonality in eight different locations while adjusting for age, calendar time and within-subject clustering of episodes by applying an adapted Serfling model approach to data from a multi-site cohort study. In the Bangladesh and Peru sites, within-subject clustering was high, with more than half of infants who experienced one rotavirus infection going on to experience a second and more than 20% experiencing a third. In the five sites that are in countries that had not introduced the rotavirus vaccine, the model predicted a primary peak in prevalence during the dry season and, in three of these, a secondary peak during the rainy season. The patterns predicted by this approach are broadly congruent with several emerging hypotheses about rotavirus transmission and are consistent for both symptomatic and asymptomatic rotavirus episodes. These findings have practical implications for programme design, but caution should be exercised in deriving inferences about the underlying pathways driving these trends, particularly when extending the approach to other pathogens.

Cost-effectiveness of tuberculosis screening and isoniazid treatment in the TB/HIV in Rio (THRio) Study.

OBJECTIVE: To estimate the incremental cost-effectiveness of tuberculosis (TB) screening and isoniazid preventive therapy (IPT) among human immunodeficiency virus (HIV) infected adults in Rio de Janeiro, Brazil. DESIGN: We used decision analysis, populated by data from a cluster-randomized trial, to project the costs (in 2010 USD) and effectiveness (in disability-adjusted life years [DALYs] averted) of training health care workers to implement the tuberculin skin test (TST), followed by IPT for TST-positive patients with no evidence of active TB. This intervention was compared to a baseline of usual care. We used time horizons of 1 year for the intervention and 20 years for disease outcomes, with all future DALYs and medical costs discounted at 3% per year. RESULTS: Providing this intervention to 100 people would avert 1.14 discounted DALYs (1.57 undiscounted DALYs). The median estimated incremental cost-effectiveness ratio was $2273 (IQR $1779-$3135) per DALY averted, less than Brazil's 2010 per capita gross domestic product (GDP) of $11,700. Results were most sensitive to the cost of providing the training. CONCLUSION: Training health care workers to screen HIV-infected adults with TST and provide IPT to those with latent tuberculous infection can be considered cost-effective relative to the Brazilian GDP per capita.

Controlled trial of active tuberculosis case finding in a Brazilian favela.

SETTING: A large, impoverished squatters' settlement (favela), Rio de Janeiro, Brazil. OBJECTIVE: To assess the community impact of active case finding for tuberculosis (TB) compared to an enhanced case-finding strategy. DESIGN: A pair-matched, cluster-randomized trial comparing household symptom screening and spot sputum collection (Arm 1) vs. distribution of an educational pamphlet (Arm 2) was performed in a large Brazilian favela. We compared TB case-notification rates, time from symptom onset to treatment start and treatment completion proportions between arms. Fourteen neighborhoods (estimated population 58,587) were pair-matched by prior TB case rates and randomly allocated to one of two interventions. TB was diagnosed using acid-fast bacilli smears. New TB cases were interviewed and clinic records were reviewed. RESULTS: A total of 193 TB cases were identified in the 14 study neighborhoods (incidence proportion 329 per 100,000 population). The case identification rate in Arm 1 was 934/100,000 person-years (py) vs. 604/100,000 py in Arm 2 (RR 1.55, 95%CI 1.10-1.99). No significant differences were found in time from cough onset to treatment start or proportion completing treatment. CONCLUSIONS: A door-to-door case-finding campaign was more effective (while ongoing) at detecting prevalent cases and influencing people to come for care than leafleting, but no differences were seen in time to treatment start or treatment completion.

Epidemiological studies of the non-specific effects of vaccines: II--methodological issues in the design and analysis of cohort studies.

We review sources of bias which can affect non-randomized cohort studies of non-specific effects of vaccines on child mortality. Using examples from the literature on non-specific effects, we describe different sources of selection and information bias, and, where possible, outline analysis strategies to mitigate or eliminate such biases.

Tuberculosis as primary cause of death among AIDS cases in Rio de Janeiro, Brazil.

SETTING: Data from the mortality database, Rio de Janeiro City (RJC) Health Department, Rio de Janeiro, Brazil. OBJECTIVES: To determine the role played by tuberculosis (TB) in Brazil's human immunodeficiency virus (HIV) positive population, we investigated the frequency of TB as the primary cause of death among HIV-positive subjects in RJC. DESIGN: Information about acquired immune-deficiency syndrome (AIDS) deaths from 1996 to 2005 in individuals aged >12 years was obtained from the Mortality Information System (SIM), and the cause of death was classified according to the International Classification of Diseases (ICD-10), through primary causes coded in Chapter I--B20 to B24 (HIV disease). RESULTS: There were 8601 AIDS-related deaths in RJC between 1996 and 2005. TB was the primary cause of death in 9.0% of all AIDS-related deaths, while Pneumocystis carinii pneumonia (PCP) accounted for 4.7%. TB cases erroneously classified under other infectious diseases may have contributed to an underestimation of the number of TB deaths among HIV-positive patients. CONCLUSION: Our study showed that TB is the leading cause of AIDS-related deaths and is responsible for twice as many deaths as PCP, in a scenario of free access to antiretrovirals. The potential benefits of TB preventive treatment and of the availability of highly active antiretroviral treatment could not be established by this analysis.

Climatic, temporal, and geographic characteristics of respiratory syncytial virus disease in a tropical island population.

Respiratory syncytial virus (RSV) is an important cause of morbidity in children worldwide, although data from equatorial regions are limited. We analysed climatic, spatial, and temporal data for children presenting to hospitals in Lombok island, Indonesia with clinical pneumonia. During the study period, 2878 children presented and 741 RSV cases were identified. In multivariate analysis with an 8-day lag, occurrence of rain was associated with 64% higher incidence of RSV disease [incidence rate ratio (IRR) 1.64, 95% confidence interval (CI) 1.13-2.38]. A 1% rise in mean relative humidity and 1 degree C increase in mean air temperature was associated with a 6% (IRR 1.06, 95% CI 1.03-1.10) and 44% (IRR 1.44, 95% CI 1.24-1.66) increase in RSV cases, respectively. Four statistically significant local clusters of RSV pneumonia were identified within the annual island-wide epidemics. This study demonstrates statistical association of monsoon-associated weather in equatorial Indonesia with RSV. Moreover, within the island-wide epidemics, localized RSV outbreaks suggest local factors influence RSV disease.

Adoption of safer infant feeding and postpartum sexual practices and their relationship to maternal HIV status and risk of acquiring HIV in Zimbabwe.

OBJECTIVE: To examine the relationships between maternal knowledge and concern about HIV status, adoption of preventive practices and risk of acquiring HIV in Zimbabwe. METHODS: Knowledge and behavioural data were collected via interview from 2595 mothers enrolled in ZVITAMBO, a randomized trial of postpartum vitamin A supplementation that also offered education on safer infant feeding and sexual practices. Mothers were tested for HIV at delivery; those uninfected at baseline were retested during study follow-up. Logistic regression methods were used to identify variables associated with adoption of preventive behaviours and, for HIV-negative mothers, their relationship to risk of acquiring HIV post-delivery. RESULTS: A total of 518 mothers (20%) reported practicing safer sex and 289 mothers (11%) reported modifying their feeding behaviour because of HIV. Fear of transmitting HIV (50.4%) and protecting the baby's health (30.9%) were the most frequently cited reasons for behaviour change. Forty-nine HIV-negative mothers acquired HIV during the first postpartum year. After taking into account other significant covariates, mothers who were concerned about their own HIV status were 1.9 times more likely (95% CI: 1.05-3.52; P = 0.03), and those reporting safer sex practices were 58% less likely to become infected (adjusted odds ratio: 0.42; 95% CI: 0.17-1.04; P = 0.06). Married women who reported practicing abstinence to prevent HIV were 3.2 times more likely to become infected than non-abstaining mothers (P = 0.01), while there were no new HIV infections among abstaining single mothers. CONCLUSIONS: Greater emphasis should be given to safer sex practices among women who test negative in mother-to-child HIV prevention programmes.

HIV-1 and HIV-2 prevalence and associated risk factors among postnatal women in Harare, Zimbabwe.

Studies of antenatal women form the predominant source of data on HIV-1 prevalence in Africa. Identifying factors associated with prevalent HIV is important in targeting diagnostic services and care. Between November 1997 and January 2000, 14,110 postnatal women from Harare, Zimbabwe were tested by ELISAs reactive to both HIV-1 and HIV-2; a subset of positive samples was confirmed with assays specific for HIV-1 and HIV-2. Baseline characteristics were elicited and modelled to identify risk factors for prevalent HIV infection. HIV-1 and HIV-2 prevalences were 32.0% (95% CI 31.2-32.8) and 1.3% (95% CI 1.1-1.5), respectively; 4% of HIV-1-positive and 99% of HIV-2-positive women were co-infected. HIV-1 prevalence increased from 0% among 14-year-olds to >45% among women aged 29-31 years, then fell to <20% among those aged>40 years. In multivariate analyses, prevalence increased with parity, was lower in married women than in single women, divorcees and widows, and higher in women with the lowest incomes and those professing no religion. Adjusted HIV-1 prevalence increased during 1998 and decreased during 1999. Age modified the effects of parity, home ownership and parental education. Among older women, prevalence was greater for women who were not homeowners. Among younger women, prevalence increased with parity and low parental education. None of these factors distinguished women co-infected with HIV-2 from those infected with HIV-1 alone. Prevalent HIV-1 infection is associated with financial insecurity and weak psychosocial support. The ZVITAMBO study apparently spanned the peak of the HIV-1 epidemic among reproductive women in Harare.

Evaluation of the indirect effects of a pneumococcal vaccine in a community-randomized study.

When a sufficiently high proportion of a population is immunized with a vaccine, reduction in secondary transmission of disease can confer significant protection to unimmunized population members. We propose a straightforward method to estimate the degree of this indirect effect of vaccination in the context of a community-randomized vaccine trial. A conditional logistic regression model that accounts for within-randomization unit correlation over time is described, which models risk of disease as a function of community-level covariates. The approach is applied to an example data set from a pneumococcal conjugate vaccine study, with study arm and immunization levels forming the covariates of interest for the investigation of indirect effects.

Combined human and porcine mass chemotherapy for the control of T. solium.

A combined (human and porcine) mass chemotherapy program was tested in a controlled design in 12 village hamlets in the Peruvian highlands. A single dose of 5 mg of praziquantel was given to eliminate intestinal taeniasis in humans, and two rounds of oxfendazole (30 mg/kg) were administered to all pigs. The total population in the study villages was 5,658 resident individuals, and the porcine population at the beginning of the study was 716 pigs. Human treatment coverage was 75%, ranging from 69% to 80%. There were only a few refusals of owners for porcine treatment of their animals. The effect of the intervention was measured by comparing incidence rates (seroconversion in pigs who were seronegative 4 months before) in treatment versus control villages, before and up to 18 months after treatment. There was a clear effect in decreasing prevalence (odds ratio, 0.51; P < 0.001) and incidence (odds ratio, 0.39; P < 0.013) in the treatment area after the intervention, which did not leave to extinction of the parasite but stabilized in slightly decreased rates persisting along the follow-up period. Mass chemotherapy was effective in decreasing infection pressure in this hyperendemic area. However, the magnitude of the effect was small and did not attain the goal of eliminating transmission.

Community level risk factors for numbers of landmine victims in Chad and Thailand.

STUDY OBJECTIVE: To determine commonalities of landmine victim risk factors in two very different countries. DESIGN AND SETTING: Data on 249 communities in Chad and 530 in Thailand were collected during 2000-2001 as part of the Global Landmine Survey. Community level variables were analysed in a series of Poisson mixture models with number of landmine victims as the dependent variable. Models developed for each country were tested on the other to investigate similarities and robustness of identification of risk factors. MAIN RESULTS: Increased community level risk was associated with population size, closeness to another community with victims, emplacement in the previous two years, blocked water or pasture, and the proximity of unexploded ordnance or anti-tank mines. In Chad, risk factors tended to be more related to identifying communities that had crossed a threshold between near zero and moderate risk; Thailand, factors were more related to increases in victim rates. CONCLUSIONS: Current systems of collecting data on community characteristics and landmine victims can provide meaningful risk factor information. Remediation approaches that focus on blockage of important resources and areas of recent, high intensity conflicts may be the most beneficial in reducing the numbers of victims.

Factors constraining adherence to referral advice for severely ill children managed by the Integrated Management of Childhood Illness approach in Imbabura Province, Ecuador.

AIM: Low referral completion rates in developing countries undermine the Integrated Management of Childhood Illness (IMCI) strategy for lowering child mortality. This study sought to identify factors constraining adherence to referral advice in a health system using the IMCI approach. METHODS: Caregivers of 160 children urgently referred to hospital were prospectively interviewed. Caregivers who accessed and did not access hospital were compared for potential referral constraining factors, including demographics, family dynamics, the severity of their child's illness, their interaction with the health system, self-perceived problems, and physical and financial access. RESULTS: 67/160 (42%) referred children did not access hospital. Six factors were associated with non-access, including two health worker actions: not being given a referral slip [adjusted odds ratio (OR)= 15.3, 95% confidence interval (95% CI) 4.4-64.6] and not being told to go to the hospital immediately (adjusted OR = 5.3, 95% CI 1.9-16.3). Receiving both of these interventions reduced the risk of not accessing hospital to 19%, from 96% for those who received neither intervention. Several indicators of illness severity, including caregivers' ranking of their children's illness severity, the presence of severe illness signs and mortality, were investigated and found not to be important explanatory factors. CONCLUSION: Providing a referral slip and counseling the caregivers of severely ill children to go to the hospital immediately appear to be powerful tools for increasing successful referral outcomes.

Randomized trial of presumptive sexually transmitted disease therapy during pregnancy in Rakai, Uganda.

OBJECTIVE: The purpose of this study was to assess presumptive sexually transmitted disease treatment on pregnancy outcome and HIV transmission. STUDY DESIGN: In a randomized trial in Rakai District, Uganda, 2070 pregnant women received presumptive sexually transmitted disease treatment 1 time during pregnancy at varying gestations, and 1963 control mothers received iron/folate and referral for syphilis. Maternal-infant sexually transmitted disease/HIV and infant outcomes were assessed. Intent-to-treat analyses estimated adjusted rate ratios and 95% confidence intervals. RESULTS: Sexually transmitted diseases were reduced: Trichomonas vaginalis (rate ratio, 0.28; 95% CI, 0.18%-0.49%), bacterial vaginosis (rate ratio, 0.78; 95% CI, 0.69-0.87), Neisseria gonorrhoeae /Chlamydia trachomatis (rate ratio, 0.43; 95% CI, 0.27-0.68), and infant ophthalmia (rate ratio, 0.37; 95% CI, 0.20-0.70). There were reduced rates of neonatal death (rate ratio, 0.83; 95% CI, 0.71-0.97), low birth weight (rate ratio, 0.68; 95% CI, 0.53-0.86), and preterm delivery (rate ratio, 0.77; 95% CI, 0.56-1.05); but there were no effects on maternal HIV acquisition or perinatal HIV transmission. CONCLUSION: Reductions of maternal sexually transmitted disease improved pregnancy outcome but not maternal HIV acquisition or perinatal HIV transmission.

Design of a group-randomized Streptococcus pneumoniae vaccine trial.

A group-randomized, double-masked, phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian populations in the southwestern United States. Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence. The trial is designed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated. Thirty-eight geographically and socially distinct areas were randomized within blocks formed by population size and geographic location. This design affords the opportunity to capture the effects of herd immunity (indirect effects) by estimating the impact of the vaccine intervention on nonimmunized infants. Group-randomized trials have challenging design and analysis features, many of which are discussed here in the context of the first such trial designed to lead to licensure of a drug or biologic in the United States.

Estimation of the indirect effect of Haemophilus influenzae type b conjugate vaccine in an American Indian population.

BACKGROUND: Oropharyngeal carriage studies of Haemophilus influenzae type b (Hib) and the rapid drop in Hib invasive disease in countries with widespread Hib conjugate vaccine immunization programmes for infants have indicated there may be significant indirect effects (herd immunity) associated with these vaccines. Our goal was to quantify the magnitude of these effects in an American Indian population during its early years of Hib immunization. METHODS: In a synthetic case-cohort study, we combined data from an efficacy trial, an immunization uptake records survey, and ongoing surveillance for Hib disease on the Navajo Nation from 1988 to 1992. Decline in the incidence of invasive Hib disease among children <2 years old was estimated via proportional hazards survival models as a function of individual immunization status and the proportion of immunized children in a community. RESULTS: The predominant vaccine during the study period was Hib-OMPC (92% of immunizations). The effectiveness of receipt of at least one dose was 97.2%. Compared to communities with 0-20% coverage with at least one dose, residence in communities with 20-40% and 40-60% coverage was associated with risk reductions of 56.5% and 73.2%, respectively. CONCLUSIONS: The results indicate substantial indirect effects of Hib-OMPC immunization may occur even at relatively low levels of immunization coverage. Countries that implement Hib immunization programmes may receive greater benefits at the community level than those due to the direct protection conferred to the individual through vaccination.

The incidence of vaccine preventable influenza-like illness and medication use among Pakistani pilgrims to the Haj in Saudi Arabia.

Over the 33-day duration of the 1999 Haj in Saudi Arabia, we collected daily health status reports for 2070 Pakistani pilgrims over 13 years of age, 54% of whom had elected to receive influenza vaccine immediately before departing for the Haj. We calculated vaccine preventable outcome incidence as the difference in attack rates between vaccinated and unvaccinated persons. The incidences of vaccine preventable influenza-like illness (sore throat in combination with cough or fever of at least 38 degrees C), fever, and any symptom of upper respiratory infection were 22, 17, and 24 per 100 pilgrims per Haj. For every 100 persons who attended the Haj, 17 had a course of antibiotics and 23 had a course of nonprescription cold medication that was preventable with influenza vaccine use. Influenza leads to significant morbidity and medication use among Haj pilgrims. Vaccine against influenza should be considered for pilgrims before entry into Saudi Arabia.

Vitamin A supplementation selectively improves the linear growth of indonesian preschool children: results from a randomized controlled trial.

BACKGROUND: Vitamin A deficiency is associated with stunting and wasting in preschool children, but vitamin A supplementation trials have not shown a consistent effect on growth. OBJECTIVE: We examined the effect of vitamin A supplementation on height and weight increments among Indonesian preschool children. DESIGN: Data were obtained from a randomized, double-masked, placebo-controlled trial of rural Javanese children aged 6-48 mo. Children received 206000 IU vitamin A (103000 IU if aged <12 mo) or placebo every 4 mo. RESULTS: High-dose vitamin A supplementation modestly improved the linear growth of the children by 0.16 cm/4 mo. The effect was modified by age, initial vitamin A status, and breast-feeding status. Vitamin A supplementation improved height by 0.10 cm/4 mo in children aged <24 mo and by 0.22 cm/4 mo in children aged >/=24 mo. The vitamin A-supplemented children with an initial serum retinol concentration <0.35 micromol/L gained 0.39 cm/4 mo more in height and 152 g/4 mo more in weight than did the placebo group. No growth response to vitamin A was found among children with an initial serum retinol concentration >/=0.35 micromol/L. In non-breast-fed children, vitamin A supplementation improved height by 0.21 cm/4 mo regardless of age. In breast-fed children, vitamin A supplementation improved linear growth by approximately 0.21 cm/4 mo among children aged >/=24 mo, but had no significant effect on the growth of children aged <24 mo. CONCLUSION: High-dose vitamin A supplementation improves the linear growth of children with very low serum retinol and the effect is modified by age and breast-feeding.

Respiratory infections reduce the growth response to vitamin A supplementation in a randomized controlled trial.

BACKGROUND: Studies on the effect of vitamin A supplementation on growth have yielded various results. It is possible that such growth is dependent on the burden of infectious diseases in the population. METHODS: We analysed data from a randomized, double-masked, placebo-controled trial to examine the role of respiratory infections and diarrhoea in modifying the growth response to vitamin A supplementation. A single high dose of vitamin A or placebo was given every 4 months to 1405 children aged 6-48 months, and 4430 child treatment cycles were used in this analysis. RESULTS: Vitamin A supplementation modestly improved linear but not ponderal growth of children who experienced little respiratory infection and especially of those who had vitamin A intake below the normative requirement (<400 RE/day). Children who received vitamin A and were free of respiratory infection grew 0.22 cm/4 months (95% CI: 0.08, 0.37) more in height than the placebo group, but those with > or =21.5% of days of respiratory infection did not show a significant growth response to vitamin A supplementation. Children who experienced no respiratory infection and had vitamin A intake <400 RE/day benefited most, gaining 0.31 cm/4 months (95% CI: 0.10, 0.52) more in height compared to the placebo group. Diarrhoea was associated with poorer growth, but did not significantly modify the effect of vitamin A supplementation on growth. CONCLUSIONS: Vitamin A supplementation improves the linear growth of children who have a low intake of vitamin A but this impact is muted with increasing levels of respiratory infections.

PIP: This randomized, double-masked, placebo-controlled trial study examined the role of respiratory infections and diarrhea in modifying the growth response to vitamin A supplementation. A total of 1405 children aged 6-48 months were given a single high dose of vitamin A or placebo every 4 months, and 4430 child treatment cycles were used in this analysis. The study was conducted in two rural subdistricts located on the southern coast of central Java, Indonesia. Analytic findings indicate that vitamin A supplementation resulted in a modest improvement in the linear and not in the ponderal growth of children. Those who had an adequate intake of 400 RE/day and were free of respiratory infection grew 0.22 cm/4 months (95% CI: 0.08, 0.37) more in height. Conversely, there were no significant growth responses to vitamin A supplementation among children with 21.5% of days or higher of respiratory infection. In addition, children who experienced no respiratory infection and had vitamin A intake below the normative requirement (400 RE/day) gained 0.31 cm/4 months (95% CI: 0.10, 0.52) more in height than the placebo group. Moreover, diarrhea was associated with poorer growth but did not modify the effect of vitamin A supplementation on growth. In conclusion, vitamin A supplementation improves linear growth in children but not among those with a high prevalence of respiratory infections.

Relative risks and population attributable fraction of incident HIV associated with symptoms of sexually transmitted diseases and treatable symptomatic sexually transmitted diseases in Rakai District, Uganda. Rakai Project Team.

OBJECTIVES: To assess the linkage of sexually transmitted disease (STD) symptoms and treatable STD to HIV incidence. DESIGN: Analysis of a randomized trial of STD control for HIV prevention, Rakai, Uganda. METHODS: Consenting adults 15-59 years of age were seen at 10-monthly home visits, interviewed regarding STD symptoms, and asked to provide samples for HIV and STD diagnoses. HIV incidence was determined in 8089 HIV-negative subjects over 10 457 person years. Adjusted rate ratios (RR) and 95% confidence intervals (CI) of HIV acquisition associated with genital ulcer disease (GUD) and discharge/dysuria were used to estimate the population attributable fraction (PAF) of HIV acquisition. HIV transmission risks associated with STD symptoms in HIV-positive partners of 167 HIV discordant couples and the numbers of sexual partners reported by HIV-positive subjects were used to estimate the PAF of HIV transmission attributable to STD. RESULTS: HIV prevalence was 16%. The risk of HIV acquisition was increased with GUD (RR 3.14; CI 1.98-4.98) and in males with discharge/dysuria (RR 2.44; CI 1.17-5.12), but not in females with discharge/dysuria. The PAF of HIV acquisition was 9.5% (CI 2.8-15.8%) with any of the three STD symptoms. The PAF for GUD was 8.8% (CI 3.7-13.8), but only 8.2% of reported GUD was caused by treatable syphilis or chancroid . The PAF for discharge/dysuria in males was 6.7% (CI 1.1-13.8), but only 25% of symptomatic males had concurrent gonorrhea or chlamydial infection. No significant differences were seen in PAF between study treatment arms. The PAF of HIV transmission associated with STD symptoms in HIV-positive persons was indirectly estimated to be 10.4%. CONCLUSION: In this mature, generalized HIV epidemic setting, most HIV seroconversion occurs without recognized STD symptoms or curable STD detected by screening. Therefore, syndromic management or other strategies of STD treatment are unlikely to substantially reduce HIV incidence in this population. However, STD is associated with significant HIV risk at the individual level, and STD management is needed to protect individuals.