Evaluation of Clinical Case Definitions for Respiratory Syncytial Virus Lower Respiratory Tract Infection in Young Children.

BACKGROUND: Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). METHODS: In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen's κ statistics. RESULTS: Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs. CONCLUSIONS: Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI. CLINICAL TRIAL REGISTRATION: NCT01995175.

Incidence of Respiratory Syncytial Virus Lower Respiratory Tract Infections During the First 2 Years of Life: A Prospective Study Across Diverse Global Settings.

BACKGROUND: The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. METHODS: This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. RESULTS: Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. CONCLUSIONS: A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175.

Respiratory viruses and influenza-like illness: Epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample.

BACKGROUND: Better population data on respiratory viruses in children in tropical and southern hemisphere countries is needed. METHODS: The epidemiology of respiratory viruses among healthy children (6 months to <10 years) with influenza-like illness (ILI) was determined in a population sample derived from an influenza vaccine trial (NCT01051661) in 17 centers in eight countries (Australia, South East Asia and Latin America). Active surveillance for ILI was conducted for approximately 1 year (between February 2010 and August 2011), with PCR analysis of nasal and throat swabs. RESULTS: 6266 children were included, of whom 2421 experienced 3717 ILI episodes. Rhinovirus/enterovirus had the highest prevalence (41.5%), followed by influenza (15.8%), adenovirus (9.8%), parainfluenza and respiratory syncytial virus (RSV) (both 9.7%), coronavirus (5.6%), human metapneumovirus (5.5%) and human bocavirus (HBov) (2.0%). Corresponding incidence per 100 person-years was 29.78, 11.34, 7.03, 6.96, 6.94, 4.00, 3.98 and 1.41. Except for influenza, respiratory virus prevalence declined with age. The incidence of medically-attended ILI associated with viral infection ranged from 1.03 (HBov) to 23.69 (rhinovirus/enterovirus). The percentage of children missing school or daycare ranged from 21.4% (HBov) to 52.1% (influenza). CONCLUSIONS: Active surveillance of healthy children provided evidence of respiratory illness burden associated with several viruses, with a substantial burden in older children.

Prevalence and Incidence of Respiratory Syncytial Virus and Other Respiratory Viral Infections in Children Aged 6 Months to 10 Years With Influenza-like Illness Enrolled in a Randomized Trial.

BACKGROUND: The high burden of respiratory syncytial virus (RSV)-associated morbidity and mortality makes vaccine development a priority. METHODS: As part of an efficacy trial of pandemic influenza vaccines (NCT01051661), RSV epidemiology in healthy children aged 6 months to <10 years at first vaccination with influenza-like illness (ILI) was evaluated in Australia, Brazil, Colombia, Costa Rica, Mexico, the Philippines, Singapore, and Thailand between February 2010 and August 2011. Active surveillance for ILI was conducted for approximately 1 year, with nasal and throat swabs analyzed by polymerase chain reaction. The prevalence and incidence of RSV among ILI episodes were calculated. RESULTS: A total of 6266 children were included, of whom 2421 experienced 3717 ILI episodes with a respiratory sample available. RSV was detected for 359 ILI episodes, a prevalence of 9.7% (95% confidence interval: 8.7-10.7). The highest prevalence was in children aged 12-23 or 24-35 months in all countries except the Philippines, where it was in children aged 6-11 months. The incidence of RSV-associated ILI was 7.0 (6.3-7.7) per 100 person-years (PY). Eighty-eight ILI episodes resulted in hospitalization, of which 8 were associated with RSV (prevalence 9.1% [4.0-17.1]; incidence 0.2 [0.1-0.3] per 100 PY). The incidence of RSV-associated ILI resulting in medical attendance was 6.0 (5.4-6.7) per 100 PY. RSV B subtypes were observed more frequently than A subtypes. CONCLUSIONS: Active surveillance demonstrated the considerable burden of RSV-associated illness that would not be identified through hospital-based surveillance, with a substantial part of the burden occurring in older infants and children.

Mammographic density and breast cancer risk: the role of the fat surrounding the fibroglandular tissue.

INTRODUCTION: Both the percent of mammographic density and absolute dense (fibroglandular) area are strong breast cancer risk factors. The role of non-dense (fat) breast tissue is not often investigated, but we hypothesize that this also influences risk. In this study we investigated the independent effects of dense and fat tissue, as well as their combined effect on postmenopausal breast cancer risk. METHODS: We performed a nested case-control study within the EPIC-NL cohort (358 postmenopausal breast cancer cases and 859 postmenopausal controls). We used multivariate logistic regression analyses to estimate breast cancer odds ratios adjusted for body mass index and other breast cancer risk factors. RESULTS: Large areas of dense (upper (Q5) vs lower quintile (Q1): OR 2.8 95% CI 1.7 to 4.8) and fat tissue (Q5 vs Q1: OR 2.4; 95% CI 1.3 to 4.2) were independently associated with higher breast cancer risk. The combined measure showed that the highest risk was found in women with both a large (above median) area of dense and fat tissue. CONCLUSIONS: Fibroglandular and breast fat tissue have independent effects on breast cancer risk. The results indicate that the non-dense tissue, which represents the local breast fat, increases risk, even independent of body mass index (BMI). When studying dense breast tissue in relation to breast cancer risk, adjustment for non-dense tissue seems to change risk estimates to a larger extent than adjustment for BMI. This indicates that adjustment for non-dense tissue should be considered when studying associations between dense areas and breast cancer risk.

The influence of a period of caloric restriction due to the Dutch famine on breast density.

Recently, we showed that short, intense caloric restriction due to the Dutch famine increased breast cancer risk in women and influenced the hormonal- and IGF-system. These systems may also affect breast density, which is one of the strongest risk factors for breast cancer. We examined the influence of the Dutch famine on breast density, using mammograms of 1,035 women. Breast size, dense and non-dense tissue and the relative density were measured on a continuous scale. Mean density was compared between three groups of ascending levels of famine-exposure. Results were adjusted for known determinants of breast density and stratified by age at exposure. There were no overall, significant differences by exposure. In unexposed compared to severely exposed women, means varied from 124 cm(2) to 121 cm(2) (p(trend) = 0.50) for breast size, from 23.4 to 21.8 cm(2) (p(trend) = 0.48) for amount of dense tissue, from 87.7 to 85.4 cm(2) (p(trend) = 0.55) for non-dense tissue and from 22.8 to 22.3% (p(trend) = 0.78) for relative density. Only among women who were younger than 10 years during the famine was the amount of non-dense tissue significantly lower with higher exposure, with 53.1 cm(2) for severely exposed compared to 77.8 cm(2) (p(trend) = 0.03) for unexposed. This group also appeared to have smaller breasts with more absolute and relative density, but not statistically significant. We observed no overall effect on breast density in women severely exposed to a short, intense caloric restriction. However, in women exposed before puberty, the non-dense area was smaller and density tended to be higher.

Comparing correlations of continuous observations from two independent populations using a sequential approach.

A sequential study design generally makes more efficient use of available information than a fixed sample counterpart of equal power. This feature is gradually being exploited by researchers in genetic and epidemiological investigations that utilize banked biological resources and in studies where time, cost and ethics are prominent considerations. Recent work in this area has focussed on the sequential analysis of matched case-control studies with a dichotomous trait. In this paper, we extend the sequential approach to a comparison of the associations within two independent groups of paired continuous observations. Such a comparison is particularly relevant in familial studies of phenotypic correlation using twins. We develop a sequential twin method based on the intraclass correlation and show that use of sequential methodology can lead to a substantial reduction in the number of observations without compromising the study error rates. Additionally, our approach permits straightforward allowance for other explanatory factors in the analysis. We illustrate our method in a sequential heritability study of dysplasia that allows for the effect of body mass index and compares monozygotes with pairs of singleton sisters.

Measurements of breast density: no ratio for a ratio.

Breast density, as visible on mammograms, is generally assessed as the occupied percentage of the breast and is a risk factor for breast cancer. Various studies have looked into the causation and alteration of relative density but the relation of a determinant with a relative measure does not allow a direct etiologic interpretation. It was our goal to compare the effects of known determinants on relative density and the absolute amounts of dense and nondense tissues. We measured the absolute and relative densities in a population of 418 postmenopausal women participating in a breast cancer screening program. The occupied surface area was calculated after manually tracing the contours of the tissues on digitized mammograms. Information on determinants was available through physical examination and questionnaires. Data were analyzed by multivariate linear regression. Age and parity were found to decrease the amount of dense tissue and the ages at menarche and menopause were found to increase it (R(2) = 13%). The amount of nondense tissue was increased by higher body mass index (BMI), age, and parity (R(2) = 43%). Relative density was affected by a combination of these factors (R(2) = 29%) with directionalities of effects that are comparable to those of dense tissue. However, the magnitudes of these effects were the resultant of the effects on dense and nondense tissues. The influence of BMI on relative density was completely due to an effect on nondense tissue. Although relative density is a relevant prognostic factor, inferences about the etiology of breast density should be made on the basis of absolute measures.