Lone Graff Stensballe

Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?

BACKGROUND Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. CONCLUSIONS Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

The causal direction in the association between respiratory syncytial virus hospitalization and asthma.

BACKGROUND Earlier studies have reported an increased risk of asthma after respiratory syncytial virus (RSV) hospitalization. Other studies found that asthmatic disposition and propensity to wheeze increase the risk of RSV hospitalization. OBJECTIVE The current study examined the causal direction of the associations between RSV hospitalization and asthma in a population-based cohort of twins. METHODS We conducted a prospective cohort study examining the associations between RSV hospitalization and asthma by using registry information on RSV hospitalization and asthma among 18,614 Danish twins born 1994 to 2003. The associations between RSV and asthma were examined in both directions: we examined the risk of asthma after RSV hospitalization, and the risk of RSV hospitalization in children with asthma in the same population-based cohort. RESULTS Asthma hospitalization after RSV hospitalization was increased as much as 6-fold to 8-fold during the first 2 months after RSV hospitalization but was no longer increased 1 year later. Asthma increased the risk of RSV hospitalization by 3-fold, and the risk was not time-dependent. Analyzing these associations on the basis of asthma defined from use of inhaled corticosteroid did not materially change the risk estimates. CONCLUSION There is a bidirectional association between severe RSV infection and asthma. Severe RSV infection is associated with a short-term increase in the risk of subsequent asthma, suggesting that RSV induce bronchial hyperresponsiveness; and asthma is associated with a long-term increased susceptibility for severe RSV disease, suggesting a host factor being responsible for the severe response to RSV infection. This suggests that severe RSV infection and asthma may share a common genetic predisposition and/or environmental exposure.

Chronic Diseases, Chromosomal Abnormalities, and Congenital Malformations as Risk Factors for Respiratory Syncytial Virus Hospitalization: A Population-Based Cohort Study

BACKGROUND Little is known about how chronic conditions other than prematurity, heart disease, and Down syndrome affect the risk and severity of hospitalization for respiratory syncytial virus (RSV). We assess the risk and severity of RSV hospitalization in children with chronic conditions in this register-based, population-based cohort study. METHODS Data on RSV tests, maternal smoking, siblings, single parenthood, mode of delivery, gestational age at birth, major surgery, asthma diagnosis, chronic conditions, and hospitalization and discharge dates were obtained from the Danish RSV database, the National Patient and Birth Registries, and the Civil Registration System. STATISTICS Cox regression models were used to estimate incidence rate ratios (IRRs) for RSV hospitalization between groups stratified by sex and date of birth. Duration of RSV hospitalization was analyzed in a linear regression and reported as geometric mean ratios. RESULTS A total of 391 983 children aged 0-23 months were included in the analysis. A total of 10,616 (2.7%) had a diagnosis for chronic disease. IRRs (95% confidence intervals) for RSV hospitalization in children with any congenital or acquired chronic condition were 2.18 (2.01-2.36) and 2.25 (1.94-2.61), respectively. Several new risk factors for RSV hospitalization, including malformations, interstitial lung disease, neuromuscular disease, liver disease, chromosomal abnormalities, congenital immunodeficiencies, and inborn errors of metabolism, were identified. Duration of RSV hospitalization was increased in many chronic conditions. CONCLUSIONS Chronic disease per se is an important risk factor for RSV hospitalization.

Atopic Disposition, Wheezing, and Subsequent Respiratory Syncytial Virus Hospitalization in Danish Children Younger Than 18 Months: A Nested Case-Control Study

OBJECTIVES. This study examined whether atopic disposition, wheezing, and atopic disorders increased the risk of hospitalizations because of respiratory syncytial virus in children between birth and 18 months of age. PATIENTS AND METHODS. Relative risks for respiratory syncytial virus hospitalization were studied in a nested 1:5 case-control design using exposure information obtained from interviews with mothers of 2564 case and 12816 control children who had been followed prospectively from birth and until 18 months of age as participants in the Danish National Birth Cohort. Information on the childrens ages at respiratory syncytial virus hospitalization, presentation of infrequent wheezing, recurrent wheezing, and atopic dermatitis were used to study these associations chronologically. RESULTS. The adjusted relative risk of respiratory syncytial virus hospitalization in the offspring was 1.11 for maternal atopic dermatitis, 1.72 for maternal asthma, and 1.23 for paternal asthma. Atopic dermatitis in the child was associated with an increased risk of subsequent respiratory syncytial virus hospitalization among infants <6 months of age. Infrequent wheezing was associated with a relative risk of subsequent respiratory syncytial virus hospitalization of 2.98 and recurrent wheezing with a relative risk of 5.90. These associations were present also if infants with medical risk factors were excluded from the analysis. CONCLUSIONS. Asthmatic disposition and wheezing were strong determinants of subsequent respiratory syncytial virus hospitalization in Danish children <18 months of age.

Birth weight and risk of asthma in 3-9 year old twins: exploring the fetal origins hypothesis

Aim To examine the relationship between birth weight and risk of asthma in a population of twins. Methods Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 was linked to information on asthma obtained from parent-completed questionnaires at age 3–9 years. Conditional logistic regression was used to calculate the risk of asthma. Results Subjects with a history of asthma at age 3–9 years weighed on average 122 g (95% CI 85 to 160) less at birth than subjects who had not developed asthma, p<0.001. There was a linear increase in asthma risk with decreasing birth weight, OR (per 100 g) 1.04 (95% CI 1.03 to 1.05), p<0.001. Within twin pairs, the lower birthweight twin had a significantly increased risk of asthma compared with the heavier co-twin (11.3% vs 9.9%), OR 1.30 (95% CI 1.10 to 1.54), p=0.002. The result remained significant after adjusting for sex, birth length and Apgar score, OR 1.31 (95% CI 1.03 to 1.65), p=0.027. The risk tended to be higher in monozygotic co-twins compared with dizygotic co-twins, especially for high birth weight differences. Conclusions Low birth weight is a risk factor for asthma independently of gestational age, sex, birth length and Apgar score, but this may be due, in part, to residual non-genetic confounding factors. This finding lends support to the “fetal origins hypothesis” suggesting undisclosed prenatal determinants for the risk of asthma.

Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze

BACKGROUND Respiratory syncytial virus (RSV) hospitalization is associated with wheeze. OBJECTIVE To examine the influence of maternally derived RSV neutralizing antibodies in cord blood on RSV hospitalization and recurrent wheeze in infancy. METHODS Among children from the Danish National Birth Cohort, we selected a subcohort of 459 randomly selected children, 408 children with RSV hospitalization, 408 children with recurrent wheeze, and all 289 children who experienced both RSV hospitalization and recurrent wheeze. The influence of cord blood RSV neutralizing antibodies was examined as predictors for (1) RSV hospitalization, (2) RSV hospitalization after recurrent wheeze, (3) recurrent wheeze, and (4) recurrent wheeze after RSV hospitalization. RESULTS Neutralizing antibody levels were inversely associated with RSV hospitalization in infants below 6 months of age (adjusted incidence rate ratio [IRR], 0.74; 95% CI, 0.62-0.87), and also inversely associated with RSV hospitalization in infants with recurrent wheeze (IRR, 0.83; 0.71-0.97). In contrast, neutralizing antibody levels were directly associated with an increased risk of recurrent wheeze in infants below 6 months of age (IRR, 1.28; 1.04-1.57) and with an increased risk of recurrent wheeze after RSV hospitalization in infants below 6 months of age (IRR, 1.44; 1.10-1.90). CONCLUSION Maternally derived RSV neutralizing antibodies protect infants against RSV hospitalization, and also when the infant has recurrent wheeze. However, high maternally derived RSV neutralizing antibody levels were associated with an increased risk of recurrent wheeze.

Seasonal Variation of Maternally Derived Respiratory Syncytial Virus Antibodies and Association with Infant Hospitalizations for Respiratory Syncytial Virus

This study used 459 prospectively sampled cord blood samples to examine the association between maternally derived respiratory syncytial virus (RSV)-neutralizing antibodies and the RSV hospitalization season in Denmark. We found a clear temporal association and suggest that RSV-neutralizing antibody level plays a role in the RSV seasonal pattern.

Increased concordance of severe respiratory syncytial virus infection in identical twins

OBJECTIVE. We estimated differences in the severity of respiratory syncytial virus infection attributable to genetic and environmental factors. METHODS. Record linkage data on hospitalizations attributable to respiratory syncytial virus infection were gathered on all twins (12346 pairs) born in Denmark between 1994 and 2003. Latent-factor models of genetic and environmental effects were fitted to the observed data by using maximal likelihood methods. RESULTS. Identical twins resembled each other significantly more than did fraternal twins for respiratory syncytial virus hospitalization (concordance rate: 0.66 vs 0.53), which suggests genetic influences on disease severity. Genetic factors accounted for 16%, family environment for 73%, and nonshared environment for 11% of the individual susceptibility to develop severe respiratory syncytial virus infection. CONCLUSIONS. The severity of respiratory syncytial virus infection is determined partly by genetic factors. This result should stimulate the search for genetic markers of disease severity.

Risk factors for respiratory syncytial virus hospitalisation in children with heart disease

Objective: To assess the risk and risk factors for respiratory syncytial virus (RSV) hospitalisation and determinants of the severity of RSV disease in children with heart disease. Methods: By using a database on RSV tests in Denmark all children with RSV diagnosed with heart disease in Denmark from January 1996 to April 2003 were identified. For each case child one control child matched for age and centre was drawn from the population of children with heart disease. Clinical information was obtained through a review of all records. Results: Data were obtained on 313 pairs. Median age at admission was 280 days (range 15–2379). In the multivariate analysis predictors of RSV hospitalisation were Down syndrome (odds ratio (OR) 3.24, 95% CI 1.80 to 5.80), cardiomyopathy (OR 5.84, 95% CI 1.26 to 27.16) and haemodynamically significant heart disease (OR 1.53, 95% CI 1.04 to 2.26). During RSV hospitalisation predictors of the need for respiratory support (supplemental oxygen, nasal continuous positive airway pressure or mechanical ventilation) were young age (relative risk (RR) 0.47, 95% CI 0.32 to 0.67 per additional year of age) and cardiac decompensation (RR 1.81, 95% CI 1.02 to 3.23). The incidence rate of RSV hospitalisation among children with any heart disease aged 0–23 months was 5.65 per 100 child-years. Conclusion: In children with heart disease risk factors for RSV admission are Down syndrome, cardiomyopathy and haemodynamically significant heart disease. Young age and cardiac decompensation are associated with a more severe course of RSV disease.

Hospitalization for Respiratory Syncytial Virus Infection and Invasive Pneumococcal Disease in Danish Children Aged <2 Years: A Population-Based Cohort Study

BACKGROUND Previous population-based studies have reported a temporal association between respiratory syncytial virus (RSV) infection and invasive pneumococcal disease (IPD). We examined this association at an individual level in the Danish population. METHODS Using registry information about hospitalization for RSV infection and IPD in Denmark, we conducted a prospective, population-based cohort study and examined the associations between hospitalization for RSV infection and IPD. RESULTS In our cohort, no persons aged > or =2 years experienced IPD within 30 days after hospitalization for RSV infection. Among children aged <2 years, children who were hospitalized for RSV infection had a significantly increased risk of IPD during the 30 days after hospitalization, compared with those who were not hospitalized for RSV infection (adjusted rate ratio, 7.1; 95% confidence interval, 3.6-14.3). Likewise, hospitalization for a non-RSV respiratory infection increased the risk of IPD during the 30 days after hospitalization (adjusted rate ratio, 4.5; 95% confidence interval, 2.0-10.0). IPD did not increase the risk of hospitalization for RSV infection among children aged <2 years. CONCLUSIONS Both recent hospitalization for RSV infection and recent hospitalization for non-RSV respiratory infection increased the risk of IPD among Danish children aged <2 years.