Kim Kristensen

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.

Epidemiology of respiratory syncytial virus infection requiring hospitalization in East Denmark.

BACKGROUND Prophylaxis against infection caused by respiratory syncytial virus (RSV) with high titered RSV immunoglobulin or humanized antibody may soon be available in Europe. OBJECTIVE To study the epidemiology of RSV infections requiring hospitalization in infants <6 months in East Denmark to provide a rational basis for decisions concerning prophylaxis against RSV. METHOD Populat ion-based retrospective review of case records of infants <6 months admitted to pediatric departments with RSV infection in East Denmark from November 1, 1995, to April 30, 1996. RESULTS Data were obtained from 459 infants. Seventy-three had predisposing conditions: prematurity, 49; pulmonary disease, 2; congenital heart disease, 7; neurologic disease, 6; others, 9. One preterm infant had bronchopulmonary dysplasia. The incidence of RSV infection requiring hospitalization in East Denmark among infants <6 months was estimated to be 34/1000/season. It was 32/1000/season among term infants and 66/ 1000/season among preterm infants (P<0.001). Infants with predisposing conditions and/or nosocomial infection (n = 24) had significantly more severe courses than otherwise healthy infants (P<0.01). One-hundred thirty infants received respiratory support by nasal continuous positive airway pressure, but only six required mechanical ventilation. No infants died. CONCLUSION The course of RSV disease in East Denmark was milder than reported elsewhere, possibly as a result of the low prevalence of bronchopulmonary dysplasia in Denmark. However, RSV constitutes a considerable burden to the Danish pediatric health care system, and therefore prophylaxis against RSV is desirable.

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.

Antibody response to Haemophilus influenzae type b capsular polysaccharide conjugated to tetanus toxoid in preterm infants.

OBJECTIVE To evaluate the antibody response to a Haemophilus influenzae type b capsular polysaccharide (HibCP) tetanus toxoid (TT) conjugate vaccine (HibCP-TT) in preterm infants. SUBJECTS Thirty-five healthy preterm infants with gestational ages (GA) from 27 to 36 weeks and birth weights from 920 to 2550 g. Controls were 37 term infants. METHODS All infants were immunized with HibCP-TT at 2, 4 and 12 months of age. Antibodies to HibCP and TT were determined at each immunization and 1 month after the second and third. RESULTS After two doses of HibCP-TT the preterm infants with GAs < or = 30 weeks (n = 8; mean GA, 29.5 weeks) had a significantly lower HibCP antibody response than the preterm infants with GAs > 30 weeks (n = 23; mean GA, 34.2 weeks) (P = 0.004), who for their part had a response not significantly different from that of the term infants. After the third dose there were no significant differences among the groups. The response to the TT part of the vaccine showed the same pattern. CONCLUSION Although the most immature infants may show an inadequate antibody response to the initial immunizations, many preterm infants can benefit from vaccination with HibCP-TT when starting immunization at the same chronologic age as term infants.

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.

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.

Antibody response to a Haemophilus influenzae type b polysaccharide tetanus toxoid conjugate vaccine in splenectomized children and adolescents.

20 children and adolescents 4-18 years old and splenectomized for various reasons (spherocytosis (n = 6), idiopathic thrombocytopenia (n = 8), other (n = 6)) were immunized once with a Haemophilus influenzae type b (Hib) polysaccharide tetanus toxoid conjugate vaccine. Prior to vaccination 10/20 patients had anticapsular antibodies below what could be considered the minimum protective level in splenectomized (0.6 micrograms/ml), whereas all obtained high antibody levels after vaccination. In addition 1 infant with congenital asplenia was vaccinated at 2,4 and 6 months of age, and was shown to respond well after the second and third injection with serum antibody concentrations of 0.84 and 10.7 micrograms/ml respectively. Because asplenic individuals have an increased risk of invasive Hib infection, these data suggest that vaccination of such individuals against Hib may be justified.

Diagnosis coding in The Danish National Patient Registry for respiratory syncytial virus infections

This national registry-based epidemiological study aimed to evaluate the usefulness of the Danish National Patient Registry (DNPR) as a tool for epidemiological studies of respiratory syncytial virus (RSV) hospitalizations. Information on RSV diagnoses in records of hospitalizations among inpatients tested for RSV in Denmark from January 1996 to May 2003 in the DNPR was validated against the RSV test result in records from the 18 laboratories testing for RSV among hospitalized patients in Denmark. Of 16,733 RSV-positive samples representing a total of 14,898 hospitalizations in the DNPR, 68% (10,111) had been registered in the DNPR with 1 or more RSV diagnoses. Age influenced the odds ratio (OR) of being coded with a RSV diagnosis among patients with a RSV positive test, hence 73% of infants compared to 57% of patients beyond infancy had been registered in the DNPR with 1 or more RSV diagnoses. The OR of being coded with a RSV diagnosis among patients with an RSV positive test was increased over the study period and was also increased by increasing length of hospitalization and by the presence of secondary diagnoses. The OR was decreased by the presence of asthma and other chronic conditions in the patients. The OR was furthermore influenced by RSV seasonality and by hospital. Taking into account a loss of 27% of RSV hospitalizations, DNPR can be used for epidemiological studies of RSV among infants in Denmark.

Caesarean Section and Hospitalization for Respiratory Syncytial Virus Infection: A Population Based Study

Background and objective: Hospitalization for respiratory syncytial virus (RSV) infection and asthma share common determinants, and meta-analyses indicate that children delivered by caesarean section (CS) are at increased risk of asthma. We aimed to investigate whether birth by CS is associated with an increased risk of hospitalization for RSV illness. Methods: This was a population-based national register-based cohort study, conducted between January, 1997 and June, 2003, which included all children born in Denmark and all hospitalizations for RSV disease in them from 0 to 23 months of age. We used Cox regression with adjustment for prematurity, asphyxia, birthweight, multiple births, single parenthood, maternal smoking during pregnancy, older siblings and asthma diagnoses up to 2 weeks before hospitalization for RSV infection, to compare the effects of acute or elective CS versus vaginal delivery, on subsequent hospitalization for RSV disease. A test for homogeneity was used to assess for effect over time. Results: 399,175 children with 10,758 hospitalizations for RSV illness were included; 31,715 were born by acute CS and 30,965 by elective CS. Adjusted hazard ratios for hospitalization for RSV infection in children born by acute CS and by elective CS were 1.09 (1.01–1.17) and 1.27 (1.19–1.36), respectively. The effect of elective CS remained unchanged throughout the first 2 years of life (P = 0.53), whereas the effect of acute CS was only present in the second year of life (P = 0.001). Conclusion: Delivery by caesarian section is associated with an increased risk of hospitalization for RSV infection. This effect continues at least throughout the first 2 years of life.

Haemophilus influenzae Type b Infections in Adults

31 cases of invasive Haemophilus influenzae type b infections occurred in adults in Denmark during a period of 2 years and 5 months corresponding to an incidence of 0.3/100,000/year. Only 6 patients had no underlying condition. The incidence of H. influenzae type b infections in adults will probably rise in the future, because the increasing use of therapeutic measures affecting the immune system will lead to an increase in the number of susceptible patients.