Palle Valentiner-Branth

Multi-country analysis of the effects of diarrhoea on childhood stunting

Diarrhoea is an important cause of death and illness among children in developing countries; however, it remains controversial as to whether diarrhoea leads to stunting. We conducted a pooled analysis of nine studies that collected daily diarrhoea morbidity and longitudinal anthropometry to determine the effects of the longitudinal history of diarrhoea prior to 24 months on stunting at age 24 months. Data covered a 20-year period and five countries. We used logistic regression to model the effect of diarrhoea on stunting. The prevalence of stunting at age 24 months varied by study (range 21-90%), as did the longitudinal history of diarrhoea prior to 24 months (incidence range 3.6-13.4 episodes per child-year, prevalence range 2.4-16.3%). The effect of diarrhoea on stunting, however, was similar across studies. The odds of stunting at age 24 months increased multiplicatively with each diarrhoeal episode and with each day of diarrhoea before 24 months (all P < 0.001). The adjusted odds of stunting increased by 1.13 for every five episodes (95% CI 1.07-1.19), and by 1.16 for every 5% unit increase in longitudinal prevalence (95% CI 1.07-1.25). In this assembled sample of 24-month-old children, the proportion of stunting attributed to >or=5 diarrhoeal episodes before 24 months was 25% (95% CI 8-38%) and that attributed to being ill with diarrhoea for >or=2% of the time before 24 months was 18% (95% CI 1-31%). These observations are consistent with the hypothesis that a higher cumulative burden of diarrhoea increases the risk of stunting.

Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study

Analyzing population-based data collected over 30 years in more than 18,000 patients with invasive pneumococcal infection, Zitta Harboe and colleagues find specific pneumococcal serotypes to be associated with increased mortality.

Impact of 13-Valent Pneumococcal Conjugate Vaccination in Invasive Pneumococcal Disease Incidence and Mortality

BACKGROUND The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) at the population level is unclear. We explored PCV13s effect in reducing invasive pneumococcal disease (IPD)-related morbidity and mortality, and whether serotype-specific changes were attributable to vaccination or expected as a part of natural, cyclical variations. METHODS This was a Danish nationwide population-based cohort study based on the linkage of laboratory surveillance data and the Danish Civil Registration System. Changes in IPD incidence and mortality during baseline (2000-2007), 7-valent pneumococcal conjugate vaccine (PCV7) (2008-2010), and PCV13 (2011-2013) periods were estimated. Predicted incidences of serotypes were estimated controlling for cyclical trends from historical patterns observed during the past 20 years. RESULTS We observed a 21% reduction (95% confidence interval [CI], 17%-25%) in IPD incidence in the total population after PCV13s introduction, and a 71% reduction (95% CI, 62%-79%) in children aged <2 years, considered as the vaccine effectiveness. We estimated a 28% reduction (95% CI, 18%-37%) in IPD-related 30-day mortality, from 3.4 deaths (95% CI, 3.2-3.6) per 100 000 population in the pre-PCV period to 2.4 (95% CI, 2.2-2.7) in the PCV13 period. The decline in mortality was observed across all age groups but was mainly related to mortality reductions in the nonvaccinated population. For serotypes 1 and 3, there were no significant changes in incidence beyond what would be expected from natural cyclical patterns. Serotype 19A significantly increased following PCV7s introduction, but the incidence declined toward baseline in 2012. CONCLUSIONS PCV13 has brought greater benefits than we had expected in our setting. We observed a further decline on IPD incidence shortly after the shift from PCV7 to PCV13 in the national immunization program. This decline was accompanied by a substantial population-level decline in pneumococcal-related mortality of nearly 30% among nonvaccinated persons.

Temporal Trends in Invasive Pneumococcal Disease and Pneumococcal Serotypes over 7 Decades

Background. Pneumococcal infections have historically played a major role in terms of morbidity and mortality. We explored historical trends of invasive pneumococcal disease (IPD) and pneumococcal serotypes in a population exposed to limited antibiotic selective pressure and conjugate pneumococcal vaccination (PCV). Methods. Retrospective cohort study based on nationwide laboratory surveillance data on IPD collected uninterruptedly in Denmark during 1938-2007. Changes in the reported incidence and trends of pneumococcal serotypes were explored using nonlinear regression analysis. Results. There were 25,502 IPD cases included in our study. The median incidence of IPD increased from 2.8 cases per 100,000 population (interquartile range [IQR], 1.5-2.6) during the first 4 decades to 15.7 cases per 100,000 population (IQR, 7-20.4) during the 1980s and 1990s, mainly attributed to an increase in the number of bacteremia cases. The incidence of meningitis remained relatively stable, with a median of 1.3 cases per 100,000 population (IQR, 0.9-1.6). The proportions of serotypes/groups 4 and 9 increased; the proportion of serotype 18C decreased; the proportions of serotypes 6, 7F, 14, and 23F remained stable; and serotype 2 nearly disappeared. Before the 1960s, serotypes 1, 2, 3, and 5 presented peaks every 2-3 years, becoming less frequent during the 1970s with peaks every 7-10 years. Between 20% and 90% of IPD in children <5 years were caused by PCV serotypes during the last 4 decades. Cases of IPD caused by serotype 19A increased before introduction of PCV. Between 1993 and 2007, the level of resistance to macrolides and β-lactams was ≤6%. Conclusions. The epidemiology of IPD and single serotypes has constantly changed over the past 7 decades. PCV serotypes appeared to dominate the pneumococcal population.

Protective immunity after natural rotavirus infection: a community cohort study of newborn children in Guinea-Bissau, west Africa.

To study the natural history of rotavirus infection and to determine the protection it confers against reinfection and diarrhea, 200 newborns in Guinea-Bissau were prospectively followed for up to 2 years. Rotavirus was detected in stool specimens collected weekly. By age 2 years, the incidence of primary rotavirus infection was 74%. In the first 3 months of life, 17% of the infections were diarrhea associated, compared with 60% at 9-11 months; after age 18 months, all infections were asymptomatic. A primary infection conferred 52% (95% confidence interval [CI], 16% to 73%) and 70% (95% CI, 29% to 87%) protection against subsequent rotavirus infection and rotavirus diarrhea, respectively. The protection was 66% (95% CI, 24% to 85%) against reinfection within the same epidemic, compared with 34% (95% CI, -29% to 67%) against reinfection in any subsequent epidemic. The high level of protection against symptomatic rotavirus infection provides an important incentive for development of a rotavirus vaccine.

Cohort study of Guinean children: Incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life

ABSTRACT We recruited 200 children shortly after birth and collected stool specimens weekly, irrespective of whether the children had diarrhea, until up to 2 years of age. All children were recruited during the first year of the study and were monitored for a median of 18.4 months. To measure pathogenicity, the odds ratio for diarrhea, adjusted for age, sex, and coinfections with other enteropathogens, was determined by logistic regression. Standard estimation of the population attributable risk indicated that rotavirus, enterotoxigenic Escherichia coli that produced only the heat-stable toxin ST, Isospora spp., Cryptosporidium parvum, Shiga toxin (Stx)-producing E. coli (STEC), and Shigella spp. or enteroinvasive E. coli were the most important contributors to diarrhea in this population. Stx2- but not Stx1-producing STEC strains were pathogenic. Enteroaggregative E. coli, diffusely adherent E. coli, and attaching-and-effacing E. coli strains, which were the most commonly isolated microorganisms, were not associated with diarrhea. For most of the microorganisms, primary infections did not confer protection against reinfection with the same organism, but some conferred protection against diarrhea from reinfection.

Seasonal influenza immunisation in Europe. Overview of recommendations and vaccination coverage for three seasons: pre-pandemic (2008/09), pandemic (2009/10) and post-pandemic (2010/11).

Since 2008, annual surveys of influenza vaccination policies, practices and coverage have been undertaken in 29 European Union (EU)/ European Economic Area (EEA) countries. After 2009, this monitored the impact of European Council recommendation to increase vaccination coverage to 75% among risk groups. This paper summarises the results of three seasonal influenza seasons: 2008/09, 2009/10 and 2010/11. In 2008/09, 27/29 countries completed the survey; in 2009/10 and 2010/11, 28/29 completed it. All or almost all countries recommended vaccination of older people (defined as those aged ≥50, ≥55, ≥59, ≥60 or ≥65 years), and people aged ≥6 months with clinical risk and healthcare workers. A total of 23 countries provided vaccination coverage data for older people, but only 7 and 10 had data for the clinical risk groups and healthcare workers, respectively. The number of countries recommending vaccination for some or all pregnant women increased from 10 in 2008/09 to 22 in 2010/11. Only three countries could report coverage among pregnant women. Seasonal influenza vaccination coverage during and after the pandemic season in older people and clinical groups remained unchanged in countries with higher coverage. However, small decreases were seen in most countries during this period. The results of the surveys indicate that most EU/EEA countries recommend influenza vaccination for the main target groups; however, only a few countries have achieved the target of 75% coverage among risk groups. Coverage among healthcare workers remained low.

Enterotoxigenic Escherichia coli Infections and Diarrhea in a Cohort of Young Children in Guinea-Bissau

In an effort to describe the natural history of enterotoxigenic Escherichia coli (ETEC) infection and diarrhea, 200 children in Guinea-Bissau, West Africa, were followed up from birth until up to age 2 years with weekly stool specimen collection, regardless of whether the children had diarrhea. ETEC isolates were tested for the presence of the porcine and human heat-stable toxins (STp and STh), the heat-labile toxin (LT), and 18 of 21 known colonization factors (CFs). The rate of primary infections increased substantially after age 3 or 6 months (depending on the type of ETEC causing the infection). The pathogenicity of STh-containing ETEC was substantially higher than that of STp-containing ETEC, and STp and STh were associated with separate sets of CFs. Small epidemics were observed, mainly caused by STh-containing ETEC. The difference in epidemic propensity, CF association, and pathogenicity suggests that STh- and STp-containing ETEC represent 2 different groups of human ETEC. Vaccines should primarily target STh-containing ETEC.

Early effectiveness of heptavalent conjugate pneumococcal vaccination on invasive pneumococcal disease after the introduction in the Danish Childhood Immunization Programme.

We evaluated the effectiveness of the heptavalent pneumococcal conjugate vaccine (PCV7) on invasive pneumococcal disease (IPD) 1 year after PCV7s introduction in the childhood immunization programme through a nationwide cohort study based on laboratory surveillance data. There was a decline in the overall incidence of IPD from 19.4 to 17.1 cases per 100,000 population (incidence rate ratios (IRR) 0.87; 95% confidence interval (CI) [0.81-0.96]), and of meningitis from 1.56 to 1.16 (IRR 0.74; 95% CI [0.57-0.97]) comparing pre-PCV7 (years 2000-2007) and PCV7 (year 2008) periods. In children <2 years, the incidence decreased from 54 to 23 cases per 100,000 (IRR 0.43; 95% CI [0.29-0.62]) and for vaccine-serotypes from 36.7 to 7.7 (IRR 0.20; 95% CI [0.09-0.38]). The incidence of IPD declined approximately 10% (IRR 0.90; 95% CI [0.84-0.97]) in patients aged >or=2 years. The case fatality was 17% in both periods. The administration of PCV7 was followed by a marked decline in the incidence of IPD in both vaccinated and non-vaccinated individuals.

Characterization of incompletely typed rotavirus strains from Guinea-Bissau: identification of G8 and G9 types and a high frequency of mixed infections

Among 167 rotavirus specimens collected from young children in a suburban area of Bissau, Guinea-Bissau, from 1996 to 1998, most identifiable strains belonged to the uncommon P[6], G2 type and approximately 50% remained incompletely typed. In the present study, 76 such strains were further characterized. Due to interprimer interaction during the standard multiplex PCR approach, modifications of this procedure were implemented. The modified analyses revealed a high frequency of G2, G8, and G9 genotypes, often combined with P[4] and/or P[6]. The Guinean G8 and G9 strains were 97 and 98%, respectively, identical to other African G8 and G9 strains. Multiple G and/or P types were identified at a high frequency (59%), including two previously undescribed mixed infections, P[4]P[6], G2G8 and P[4]P[6], G2G9. These mixed infections most likely represent naturally occurring reassortance of rotavirus strains. Detection of such strains among the previously incompletely typed strains indicates a potential underestimation of mixed infections, if only a standard multiplex PCR procedure is followed. Furthermore cross-priming of the G3 primer with the G8 primer binding site and silent mutations at the P[4] and P[6] primer binding sites were detected. These findings highlight the need for regular evaluation of the multiplex primer PCR method and typing primers. The high frequency of uncommon as well as reassortant rotavirus strains in countries where rotavirus is an important cause of child mortality underscores the need for extensive strain surveillance as a basis to develop appropriate rotavirus vaccine candidates.