What are the implications for childhood pneumonia of successfully introducing Hib and pneumococcal vaccines in developing countries?

The authors look to the future and imagine the implications of a successful vaccination campaign againstH. influenzae type b and pneumococcus

The Malaria-High Blood Pressure Hypothesis.

RATIONALE: Several studies have demonstrated links between infectious diseases and cardiovascular conditions. Malaria and hypertension are widespread in many low- and middle-income countries, but the possible link between them has not been considered. OBJECTIVE: In this article, we outline the basis for a possible link between malaria and hypertension and discuss how the hypothesis could be confirmed or refuted. METHODS AND RESULTS: We reviewed published literature on factors associated with hypertension and checked whether any of these were also associated with malaria. We then considered various study designs that could be used to test the hypothesis. Malaria causes low birth weight, malnutrition, and inflammation, all of which are associated with hypertension in high-income countries. The hypothetical link between malaria and hypertension can be tested through the use of ecological, cohort, or Mendelian randomization studies, each of which poses specific challenges. CONCLUSIONS: Confirmation of the existence of a causative link with malaria would be a paradigm shift in efforts to prevent and control hypertension and would stimulate wider research on the links between infectious and noncommunicable disease

Analysing Interrupted Time Series with a Control

Abstract Interrupted time series are increasingly being used to evaluate the population-wide implementation of public health interventions. However, the resulting estimates of intervention impact can be severely biased if underlying disease trends are not adequately accounted for. Control series offer a potential solution to this problem, but there is little guidance on how to use them to produce trend-adjusted estimates. To address this lack of guidance, we show how interrupted time series can be analysed when the control and intervention series share confounders, i. e. when they share a common trend. We show that the intervention effect can be estimated by subtracting the control series from the intervention series and analysing the difference using linear regression or, if a log-linear model is assumed, by including the control series as an offset in a Poisson regression with robust standard errors. The methods are illustrated with two examples.</jats:p

Effect of Maternally Derived Anti-protein and Anticapsular IgG Antibodies on the Rate of Acquisition of Nasopharyngeal Carriage of Pneumococcus in Newborns.

Background: In developing countries, introduction of pneumococcal conjugate vaccine has not eliminated circulation of vaccine serotypes. Vaccinating pregnant mothers to increase antibody concentrations in their newborn infants may reduce the acquisition of pneumococcal carriage and subsequent risk of disease. We explored the efficacy of passive immunity, attributable to anti-protein and anticapsular pneumococcal antibodies, against acquisition of carriage. Methods: We examined the rate of nasopharyngeal acquisition of pneumococci in the first 90 days of life associated with varying anticapsular and anti-protein antibody concentrations in infant cord/maternal venous blood in Kilifi, Kenya. We used multivariable Cox proportional hazard models to estimate continuous functions relating acquisition of nasopharyngeal carriage to the concentration of maternally derived antibody. Results: Cord blood or maternal venous samples were collected from 976 mother-infant pairs. Pneumococci were acquired 561 times during 33,905 person-days of follow-up. Increasing concentrations of anti-protein antibodies were associated with either a reduction (PhtD1, PspAFam2, Spr0096, StkP) or, paradoxically, an increase (CbpA, LytC, PcpA, PiaA, PspAFam1, RrgBT4) in acquisition rate. We observed a nonsignificant reduction in the incidence of homologous carriage acquisition with high concentrations of maternally derived anticapsular antibodies to 5 serotypes (6A, 6B, 14, 19F, and 23F). Conclusion: The protective efficacy of several anti-protein antibodies supports the strategy of maternal vaccination to protect young infants from carriage and invasive disease. We were not able to demonstrate that passive anticapsular antibodies were protective against carriage acquisition at naturally occurring concentrations though it remains possible they may do so at the higher concentrations elicited by vaccination

Incidence and severity of respiratory syncytial virus pneumonia in rural Kenyan children identified through hospital surveillance

Background.Although necessary for developing a rationale for vaccination, the burden of severe respiratory syncytial virus (RSV) disease in children in resource‐poor settings remains poorly defined. Methods.We conducted prospective surveillance of severe and very severe pneumonia in children aged <5 years admitted from 2002 through 2007 to Kilifi district hospital in coastal Kenya. Nasal specimens were screened for RSV antigen by immunofluorescence. Incidence rates were estimated for the well‐defined population. Results.Of 25,149 hospital admissions, 7359 patients (29%) had severe or very severe pneumonia, of whom 6026 (82%) were enrolled. RSV prevalence was 15% (20% among infants) and 27% during epidemics (32% among infants). The proportion of case patients aged 3 months was 65%, and the proportion aged 6 months was 43%. Average annual hospitalization rates were 293 hospitalizations per 100,000 children aged <5 years (95% confidence interval, 271–371 hospitalizations per 100,000 children aged <5 years) and 1107 hospitalizations per 100,000 infants (95% confidence interval, 1012–1211 hospitalizations per 100,000 infants). Hospital admission rates were double in the region close to the hospital. Few patients with RSV infection had life‐threatening clinical features or concurrent serious illnesses, and the associated mortality was 2.2%. Conclusions.In this low‐income setting, rates of hospital admission with RSV‐associated pneumonia are substantial; they are comparable to estimates from the United States but considerably underestimate the burden in the full community. An effective vaccine for children aged >2 months (outside the age group of poor responders) could prevent a large portion of RSV disease. Severity data suggest that the justification for RSV vaccination will be based on the prevention of morbidity, not mortality

Clinical and Epidemiological Implications of 24-Hour Ambulatory Blood Pressure Monitoring for the Diagnosis of Hypertension in Kenyan Adults: A Population-Based Study.

BACKGROUND: The clinical and epidemiological implications of using ambulatory blood pressure monitoring (ABPM) for the diagnosis of hypertension have not been studied at a population level in sub-Saharan Africa. We examined the impact of ABPM use among Kenyan adults. METHODS AND RESULTS: We performed a nested case-control study of diagnostic accuracy. We selected an age-stratified random sample of 1248 adults from the list of residents of the Kilifi Health and Demographic Surveillance System in Kenya. All participants underwent a screening blood pressure (BP) measurement. All those with screening BP ≥140/90 mm Hg and a random subset of those with screening BP <140/90 mm Hg were invited to undergo ABPM. Based on the 2 tests, participants were categorized as sustained hypertensive, masked hypertensive, "white coat" hypertensive, or normotensive. Analyses were weighted by the probability of undergoing ABPM. Screening BP ≥140/90 mm Hg was present in 359 of 986 participants, translating to a crude population prevalence of 23.1% (95% CI 16.5-31.5%). Age standardized prevalence of screening BP ≥140/90 mm Hg was 26.5% (95% CI 19.3-35.6%). On ABPM, 186 of 415 participants were confirmed to be hypertensive, with crude prevalence of 15.6% (95% CI 9.4-23.1%) and age-standardized prevalence of 17.1% (95% CI 11.0-24.4%). Age-standardized prevalence of masked and white coat hypertension were 7.6% (95% CI 2.8-13.7%) and 3.8% (95% CI 1.7-6.1%), respectively. The sensitivity and specificity of screening BP measurements were 80% (95% CI 73-86%) and 84% (95% CI 79-88%), respectively. BP indices and validity measures showed strong age-related trends. CONCLUSIONS: Screening BP measurement significantly overestimated hypertension prevalence while failing to identify ≈50% of true hypertension diagnosed by ABPM. Our findings suggest significant clinical and epidemiological benefits of ABPM use for diagnosing hypertension in Kenyan adults

Pneumococcal conjugate vaccine induced IgG and nasopharyngeal carriage of pneumococci: Hyporesponsiveness and immune correlates of protection for carriage.

BACKGROUND: Prior studies have demonstrated hyporesponsiveness to pneumococcal conjugate vaccines (PCVs) when administered in the presence of homologous carriage. This may be substantially more important in Africa where carriage prevalence is high. Deriving a correlate of protection (CoP) for carriage is important in guiding the future use of extended PCVs as population control of pneumococcal disease by vaccination is now focused principally on its indirect effect. We therefore explored the complex relationship between existing carriage and vaccine responsiveness, and between serum IgG levels and risk of acquisition. METHODS: We undertook secondary analyses of data from two previously published clinical trials of the safety and immunogenicity of PCV in Kenya. We compared responses to vaccination between serotype-specific carriers and non-carriers at vaccination. We assessed the risk of carriage acquisition in relation to PCV-induced serum IgG levels using either a step- or continuous-risk function. RESULTS: For newborns, the immune response among carriers was 51-82% lower than that among non-carriers, depending on serotype. Among toddlers, for serotypes 6B, 14 and 19F the post-vaccination response among carriers was lower by between 29 and 70%. The estimated CoP against acquisition ranged from 0.26 to 1.93?g/mL across serotypes, however, these thresholds could not be distinguished statistically from a model with constant probability of carriage independent of assay value. CONCLUSION: We have confirmed hyporesponsiveness in an equatorial African setting in both infants and toddlers. Population responses to vaccination are likely to improve with time as carriage prevalence of vaccine serotypes is reduced. We have not found clear correlates of protection against carriage acquisition among toddlers in this population. Assessing the potential of new vaccines through the use of CoP against carriage is still difficult as there are no clear-cut serotype specific correlates

Making standards for quantitative real-time pneumococcal PCR.

Quantitative lytA PCR is often performed using in-house standards. We hypothesised equivalence when measuring a standard suspension of Streptococcus pneumoniae by colony-forming-units (CFU) or genome-copies. Median (IQR) ratio of CFU/genome-copies was 0.19 (0.1-1.2). Genome-copies were less variable than CFU, but the discrepancy between the methods highlights challenges with absolute quantification

Incidence and clinical characteristics of group A rotavirus infections among children admitted to hospital in Kilifi, Kenya

Background Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention. Methods and Findings Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as "cases" if admitted with diarrhoea, and "controls" if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9–4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275–1,600) in infants and 478 (437–521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17%) and severe electrolyte imbalance except hyponatraemia. In-hospital case fatality was 2% among rotavirus-positive and 9% among rotavirus-negative children. Conclusions In Kilifi > 2% of children are admitted to hospital with group A rotavirus diarrhoea in the first 5 y of life. This translates into over 28,000 vaccine-preventable hospitalisations per year across Kenya, and is likely to be a considerable underestimate. Group A rotavirus diarrhoea is associated with acute life-threatening metabolic derangement in otherwise healthy children. Although mortality is low in this clinical research setting this may not be generally true in African hospitals lacking rapid and appropriate management