Hospitalisation for lower respiratory tract infection in children in the province of Quebec, Canada, before and during the pneumococcal conjugate vaccine era.

Streptococcus pneumoniae is an important cause of community-acquired pneumonia and pneumococcal conjugate vaccines (PCVs) may reduce this burden. This study's goal was to analyse trends in lower respiratory tract infections (LRTI) hospitalisations before and during a routine vaccination programme targeting all newborns with PCV was started in the province of Quebec, Canada in December 2004. The study population included hospital admissions with a main diagnosis of LRTI among 6-59 month-old Quebec residents from April 2000 to December 2014. Trends in proportions and rates were analysed using Cochran-Armitage tests and Poisson regression models. We observed a general downward trend in all LTRI hospitalisations rate: from 11·55/1000 person-years in 2000-2001 to 9·59/1000 in 2013-2014, a 17·0% reduction, which started before the introduction of PCV vaccination. Downward trends in hospitalisation rates were more pronounced for all-cause of pneumonia (minus 17·8%) than for bronchiolitis (minus 15·4%). There was also a decrease in the mean duration of hospital stay. There was little evidence that all-cause pneumonia decreased over the study period due mainly to the introduction of PCVs. Trends may be related to changes in clinical practice. This study casts doubt on the interpretation of ecological analyses of the implementation of PCV vaccination programmes.

Predictors of hospitalization for lower respiratory tract infection in children aged <2 years in the province of Quebec, Canada.

Young age, adverse environmental conditions and infectious agents are established risk factors of lower respiratory tract infection (LRTI), whereas pneumococcal conjugate vaccines may be protective. To explore their relative role as predictors of hospitalizations under the continental climate prevailing in the province of Quebec, Canada, an ecological study was performed. Records with a main diagnosis of LRTI in children born during 2007-2010 and observed up to their second-year anniversary were extracted from the provincial hospital administrative database. Respiratory virus surveillance data and statistics on ambient air temperature were obtained. Vaccine use in different birth cohorts was derived from the Quebec City Immunization Registry. Additive and multiplicative Poisson regression models were applied to estimate attributable fractions. Age, month of birth, ambient temperature, and respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza-positive test proportions were significant predictors of LRTI hospitalizations. No substantial differences were observed in cohorts exposed to the 7-valent or 10-valent pneumococcal conjugate vaccines. In the additive model, the fraction of hospitalizations explained by temperature variation was 37%, whereas RSV circulation explained 28%, hMPV 4% and influenza 1%. Complex interplay between biological, environmental and social mechanisms may explain the important role of ambient air temperature in predicting LRTI hospitalization risk in young children.

Clinicians' opinions on new vaccination programs implementation.

In Canada, several new vaccines were recently approved for clinical use or are expected to be soon. Decision-makers are faced with the choice whether or not to include these vaccines in publicly funded vaccination programs. The aim of this study was to assess Canadian pediatricians' and family physicians' opinions regarding 7 new vaccines, and perceived priority for the introduction of new programs. A self-administered, anonymous, mail-based questionnaire was sent during fall 2009 to a random sample of 1182 family physicians and to all 1852 Canadian pediatricians. Responses to 8 statements regarding frequency and severity of the diseases, efficacy and safety of the vaccines as well as feasibility of immunization programs were used to calculate priority scores to rank the 7 potential new vaccination programs (calculated scores ranging from 0 to 100). Overall response rate was 43%. The majority of respondents perceived the health and economic burden of diseases prevented by the seven new vaccines as important and considered new vaccines to be safe and effective. More than 90% of physicians strongly agreed or agreed that the new vaccines would be or are currently well accepted by the public and by the health professionals who administer vaccines, except for the HPV and rotavirus vaccines (respectively 30% and 29% strongly agreed or agreed). Mean priority scores were: 77.4 out of 100 for the measles, mumps, rubella and varicella (MMRV) combined vaccine; 75.6 for the hexavalent (DTaP-IPV-Hib-HBV) vaccine; 73.1 for the new pneumococcal conjugate vaccines; 69.8 for the meningococcal ACYW135; 68.9 for the combined hepatitis A and B; 63.5 for the human papillomavirus vaccine and 56.9 for the rotavirus vaccine. Health professionals' opinion is an important element to consider in the decision-making process regarding implementation of new immunization programs. Without health professional support, the introduction of a new vaccination program may be unsuccessful. In this study, the MMRV and the hexavalent (DTaP-IPV-Hib-HBV) vaccines received the highest ratings.

Canadian paediatricians' opinions on rotavirus vaccination.

Rotavirus is the leading cause of dehydration and hospitalization due to gastroenteritis (GE) in young children. Almost all children are affected by the age of 5 years. Two safe and effective rotavirus vaccines are available for clinical use in Canada. In the context where rotavirus vaccination is recommended, but not publicly funded, we have assessed paediatricians' knowledge, attitudes and beliefs (KAB) regarding rotavirus disease and its prevention by vaccination. A self-administered anonymous questionnaire based upon the Health Belief Model and the Analytical framework for immunization programs was mailed to all 1852 Canadian paediatricians. The response rate was 50%. The majority of respondents rated consequences of rotavirus infection for young patients as moderate. Sixty-six percent considered that rotavirus disease occur frequently without vaccination and 62% estimated that the disease generates a significant economic burden. Sixty-nine percent of respondents considered rotavirus vaccines to be safe and 61%, to be effective. The reduction of severe GE cases was seen as the main benefit of rotavirus vaccination, while the risk of adverse events was the principal perceived barrier. Fifty-three percent (53%) indicated a strong intention to recommend rotavirus vaccines. In multivariate analysis, main determinant of paediatricians' intention to recommend rotavirus vaccines was the perceived health and economic burden of rotavirus diseases (partial R(2)=0.49, p<0.0001). More than half of surveyed paediatricians were willing to recommend rotavirus vaccines to their patients, but the proportion of respondents who had a strong intention to do so remains low when compared to several other new vaccines. As with other new vaccines, rotavirus vaccine uptake risks to remain low in Canada as long as it is not publicly funded.

Variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease: a review of the PICNIC RSV database. Pediatric Investigators Collaborative Network on Infections in Canada.

OBJECTIVE: We wished to compare outcomes of respiratory syncytial virus (RSV) infection in children with bronchopulmonary dysplasia (BPD) with those with other pulmonary disorders: cystic fibrosis, recurrent aspiration pneumonitis, pulmonary malformation, neurogenic disorders interfering with pulmonary toilet, and tracheoesophageal fistula. METHODS: Children with RSV infection hospitalized at seven Canadian pediatric tertiary care hospitals in 1993 through 1994 and 9 hospitals in 1994 through 1995 were enrolled and prospectively followed. This study is a secondary analysis of data from this prospective cohort. RESULTS: Of the 1516 patients enrolled the outcomes of 159 with preexisting lung disorders before RSV lower respiratory tract infection constitute this report. There were no significant differences among the 7 groups (BPD, cystic fibrosis, recurrent aspiration pneumonitis, pulmonary malformation, neurogenic disorders interfering with pulmonary toilet, tracheoesophageal fistula, other) for the morbidity measures: duration of hospitalization, intensive care unit (ICU) admission, duration of ICU stay, mechanical ventilation and duration of mechanical ventilation. Patients using home oxygen were more likely to be admitted to the ICU than those who had never or previously used home oxygen (current 57.1%, past 23.8%, never 33.3%, P = 0.03). CONCLUSIONS: Children with other underlying diseases have morbidity similar to those with BPD. Prophylactic interventions against RSV should also be studied in these groups.

Nosocomial respiratory syncytial virus infection in Canadian pediatric hospitals: a Pediatric Investigators Collaborative Network on Infections in Canada Study.

OBJECTIVE: To determine nosocomial transmission of respiratory syncytial virus (RSV) in Canadian pediatric hospitals, outcomes associated with nosocomial disease, and infection control practices. DESIGN: A prospective cohort study in the 1992 to 1994 winter respiratory seasons. SETTING: Nine Canadian pediatric university-affiliated hospitals. PARTICIPANTS: Hospitalized children with symptoms of lower respiratory tract infection (at least one of cough, wheezing, dyspnea, tachypnea, and apnea) and RSV antigen identified in a nasopharyngeal aspirate. RESULTS: Of 1516 children, 91 (6%) had nosocomial RSV (NRSV), defined as symptoms of lower respiratory tract infection and RSV antigen beginning >72 hours after admission. The nosocomial ratio (NRSV/[com-munity-acquired RSV {CARSV})] + NRSV) varied by site from 2.8% to 13%. The median length of stay attributable to RSV for community-acquired illness was 5 days, but 10 days for nosocomial illness. Four children with NRSV (4. 4%) died within 2 weeks of infection, compared with 6 (0.42%) with CARSV (relative risk = 10.4, 95% confidence interval: 3.0, 36.4). All sites isolated RSV-positive patients in single rooms or cohorted them. In a multivariate model, no particular isolation policy was associated with decreased nosocomial ratio, but gowning to enter the room was associated with increased risk of RSV transmission (incidence rate ratio 2.81; confidence interval: 1.65, 4.77). CONCLUSIONS: RSV transmission risk in Canadian pediatric hospitals is generally low. Although use of barrier methods varies, all sites cohort or isolate RSV-positive patients in single rooms. Children with risk factors for severe disease who acquire infection nosocomially have prolonged stays and excess mortality.

Economic evaluation of respiratory syncytial virus infection in Canadian children: a Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study.

OBJECTIVES: To quantify the cost and distribution of health care resources consumed annually in management of Canadian children from birth to 4 years of age with respiratory syncytial virus (RSV) infection. STUDY DESIGN: Estimates of direct medical expenditures (in 1993 U.S. dollars) were collected from a prospective cohort study of hospitalized children with RSV and from national and provincial databases. RESULTS: The annual cost of RSV-associated illness was almost $18 million. The largest component of direct expenditures (62%) was for inpatient care for the estimated 0.7% of all infected children ill enough to require admission. Physician fees comprised only 4% of inpatient expenses. Expenditures for ambulatory patients accounted for 38% of direct costs. CONCLUSIONS: The greatest reductions in the economic cost of RSV infections will be found in interventions that reduce duration of or prevent hospital stay. Costs for management of RSV infection in children in the Canadian health care system are considerably less than charges reported in the United States.

PICNIC (Pediatric Investigators Collaborative Network on Infections in Canada) study of the role of age and respiratory syncytial virus neutralizing antibody on respiratory syncytial virus illness in patients with underlying heart or lung disease.

OBJECTIVE: To determine the effects of age and respiratory syncytial virus (RSV) antibody status on frequency and severity of RSV infections in children with underlying heart or lung disease. DESIGN: Cohort study conducted during two consecutive RSV seasons. SETTING: Ambulatory patients at eight Canadian pediatric tertiary care centers. METHODS: Subjects under 3 years old with underlying heart disease who were digoxin-dependent or had not received corrective cardiac surgery or with underlying lung disease were enrolled. Demographic information and an acute sera for RSV neutralizing antibody was obtained on enrollment. Weekly telephone follow-up consisting of a respiratory illness questionnaire was followed with a home visit to obtain a nasopharyngeal aspirate when there was new onset of respiratory symptoms. The specimen was used to detect RSV antigen. RSV illnesses were grouped as upper or lower respiratory tract infection (LRI) based on clinical and radiographic findings. RSV hospitalizations were considered to be those RSV infections that resulted in hospitalization. RESULTS: Of 427 enrolled subjects, 160 had underlying lung disease only, 253 had underlying heart disease only, and 14 had both. Eleven percent and 12% of lung and heart disease groups, respectively, had an RSV LRI. Three percent and 6% of lung and heart disease groups, respectively, were hospitalized with RSV infection. A significant decrease in frequency of RSV LRI and RSV hospitalization occurred with increasing age, with a major drop in those older than 1 year vs those younger than 1 year. Acute sera were available from 422 subjects. Geometric mean RSV antibody titers demonstrated a U-shaped distribution with increasing age. The trend to lower antibody concentrations in premature infants did not reach statistical significance. The frequency of RSV infection and RSV LRI was lower in patients with antibody at a titer more than 100, although the difference for RSV hospitalization was not statistically significant. These differences remained significant after age adjustment. CONCLUSION: Both age and RSV antibody status impact on RSV illness and LRI. Reduction in illness frequency with increasing age may lead to more informed targeting of those children most likely to benefit from RSV immune globulin prophylaxis.

Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection.

OBJECTIVE: To describe differences in patients hospitalized with respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) at nine Canadian tertiary care hospitals. In addition, this study describes the variation in use of drug and other interventions. METHODS: Data on patients hospitalized with RSV LRI and their outcomes were prospectively collected. Demographic data were obtained on enrollment by center study nurses. Data recorded daily included clinical assessment, oxygen saturation determination, and interventions (bronchodilators, steroids, ribavirin, antibiotics, intensive care, and mechanical ventilation) received during the day. Patients were divided into those with underlying diseases including congenital heart disease, chronic lung disease, immunodeficiency, or multiple congenital anomalies and those who were previously healthy. Mean RSV-associated length of stay and the proportion of patients receiving each intervention in each group were determined by hospital. RESULTS: A total of 1516 patients were enrolled at nine hospitals during January 1 to June 30, 1993, and January 1 to April 30, 1994. Significant differences were observed among hospitals in the proportion of patients with underlying disease, postnatal age less than 6 weeks, hypoxia, and pulmonary infiltrate on chest radiograph. The mean length of stay varied among hospitals from 8.6 to 11.8 days and 4.6 to 6.7 days in compromised and previously healthy patients, respectively. Except for receipt of bronchodilators, compromised patients were significantly more likely to receive interventions than previously healthy patients. There was variation among hospitals in receipt of most interventions in compromised and previously healthy patients. This variation was statistically significant for previously healthy patients but not statistically significant in those with underlying disease, because the numbers of patients in the latter group were much smaller. The magnitude of the variation for each intervention, however, was not different between those with underlying disease compared with previously healthy patients. CONCLUSION: Differences exist among tertiary pediatric hospitals in the nature of the patients admitted with RSV LRI. Variation occurred in the use of five interventions among the hospitals, regardless of whether the patient had underlying illness or was previously healthy. Given their current widespread use, high cost, and potential side effects, randomized clinical trials are needed to determine the efficacy of different drug treatments used to treat infants hospitalized with RSV.

Study of interobserver reliability in clinical assessment of RSV lower respiratory illness: a Pediatric Investigators Collaborative Network for Infections in Canada (PICNIC) study.

Randomized trials of ribavirin therapy have used clinical scores to assess illness severity. Little information on agreement for these findings between observers has been published. We decided to determine interobserver agreement for (1) a history for apnea or respiratory failure; (2) assessment of cyanosis, respiratory rate, retractions, and oximetry; and (3) determination of reason for hospitalization (requirement for medications, supportive care, underlying illness, poor home environment). At eight centers 137 RSV-infected patients were assessed by two observers blinded to the assessments by others with no interventions made between assessments. Observations were categorized, and agreement was summarized as percentage of observed agreement, Pearson correlation, or as a kappa statistic. Observed agreement for a history of either apnea or a respiratory arrest was at least 90% at all centers, with seven of the eight centers in total agreement. At all centers except one, the agreement on the reason why the patient remained in hospital was at least 80%. The observed agreement for assessing cyanosis was at least 94% at all eight centers. The correlation coefficient for respiratory rate varied from 0.42 to 0.97 across centers. The kappa values for agreement beyond chance for retractions varied from 0.05 to 1.00. The kappa values for oxygen saturation measures varied from 0.31 to 0.70. Although not statistically significant, there appeared to be more variation as the time between assessments increased. In conclusion, agreement for historical findings and assessment of cyanosis was high. However, there was wide variation in agreement in the other assessments. Training to ensure consistent and reproducible assessment by different examiners will be necessary if these findings are to be used as outcome variables in clinical trials.

Possible red-man syndrome associated with systemic absorption of oral vancomycin in a child with normal renal function.

OBJECTIVE: To report possible red-man syndrome (RMS) associated with oral administration of vancomycin. CASE SUMMARY: A 23-month-old child with acute myeloblastic leukemia developed symptoms compatible with RMS while receiving oral vancomycin for suspected Clostridium difficile colitis. Serum concentrations of vancomycin, measured at the time of the clinical episode, demonstrated significant oral absorption of the drug. Serum concentrations of vancomycin decreased later, implying a possible decrease in absorption, after the patient's neutrophil count returned to normal. The child later experienced another clinical episode compatible with RMS while vancomycin was being administered intravenously for suspected sepsis. DISCUSSION: There is no published report of RMS following oral administration of vancomycin. The reaction described took place while the child was neutropenic. Because of the absence of any significant renal function alteration that could explain the importance of the serum concentrations observed, we assume that C. difficile, neutropenia-, and chemotherapy-associated colitis may have resulted in extensive intestinal lesions, leading to an increased amount of vancomycin being systemically absorbed. This increased absorption during profound neutropenia may have been sufficient to exceed a purported threshold, leading to RMS. CONCLUSIONS: This case demonstrates that significant absorption of vancomycin may occur in neutropenic patients with normal renal function, and that it may be accompanied by RMS, usually associated with rapid infusions or large parenteral doses of the drug.

Detection of antibodies to herpes simplex virus type 2 with a mammalian cell line expressing glycoprotein gG-2.

The gene (US4) coding for herpes simplex virus type 2 (HSV-2) glycoprotein G (gG-2) was cloned and constitutively expressed in Chinese hamster ovary (CHO) cells. The expression vector containing the dihydrofolate reductase (dhfr) gene, and the HSV-2 US4 gene under the control of the Simian virus 40 early promoter (SV40 EP), was transfected into dhfr-deficient CHO cells. The transfected cells were selected and amplified using methotrexate (MTX). To demonstrate that the gG-2 produced in these transformed cells had antigenic determinants in common with the native glycoprotein, CHO cells expressing gG-2 were used in an immunofluorescent assay (IFA) for the detection of HSV-2 type-specific antibodies in human serum samples. Seven of eight serum samples from adults with prior episodes of culture proven HSV-2 infections were found to be positive by the IFA method whereas none of seven serum samples from young children with culture documented HSV-1 infections were positive by IFA. Thus the recombinant CHO : gG-2 cells have diagnostic utility in an HSV-2 specific serologic assay.

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus.

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.

A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy.

In order to study the epidemiology of herpes simplex type 2 (HSV-2) infections during pregnancy, we used an enzyme immunoassay to detect type-specific antibodies to HSV-2 glycoprotein G in serial blood samples obtained from a cohort of 1891 pregnant women. Blood samples obtained at about 17 and 32 weeks of gestation and at the time of delivery were assessed for antibody to HSV-2 glycoprotein G in order to evaluate the prevalence of past infections with HSV-2 and the rate of acquisition of HSV-2 infection during pregnancy. Three hundred eleven pregnant women (16.5%) were found to have had past infections with HSV-2. Four of the 1580 women who were initially seronegative developed antibodies to HSV-2 during pregnancy. The annualized rate of acquisition of HSV-2 infection in pregnant women was 0.58%. Three of four women had asymptomatic primary infections; all of the women had preexisting HSV-1 immunity. None of the women or their infants experienced any adverse consequences of gestational herpes. Based upon our very limited number of observations to date, asymptomatic primary episodes occurring in women with previous HSV-1 immunity may be of less consequence to the fetus and neonate than symptomatic true primary HSV-2 infections.

Use of routine viral cultures at delivery to identify neonates exposed to herpes simplex virus.

We obtained specimens for viral culture from mothers, infants, or both at the time of 6904 deliveries, without regard to the mothers' history of genital herpes. Herpes simplex virus (HSV) was recovered in cultured specimens from 14 of the 6904 deliveries (0.20 percent); all 14 mothers were asymptomatic. All viral isolates were herpes simplex virus type 2 (HSV-2). Only 1 of the 14 women (7 percent) had a history of genital herpes, whereas 12 (86 percent) had serologic evidence of a previous infection with HSV-2. None of the infants born to these 12 women contracted neonatal herpes. However, one of the two infants born to women with serologic evidence of a primary HSV infection at the time of delivery contracted neonatal herpes. Our findings show that most infants at risk of exposure to HSV at delivery will not be identified if concern about asymptomatic shedding of virus is limited to women with a history of genital herpes infection. Most neonatal exposure to an asymptomatic maternal HSV infection at delivery is not predictable or preventable. Therefore, physicians caring for newborns need to consider neonatal herpes in the differential diagnosis when infants become ill during the first weeks of life, regardless of the presence or absence of identifiable risk factors for HSV infection.

Comparative bactericidal activity of cefixime, carumonam, enoxacin and roxithromycin with those of other antibiotics against resistant Haemophilus influenzae including beta-lactam tolerant strains.

One hundred isolates of Haemophilus influenzae including 50 beta-lactamase producing, five ampicillin-resistant non-beta-lactamase producing and five beta-lactam tolerant strains were tested for susceptibility (MICs and MBCs) to ampicillin, aztreonam, carumonam, cefixime, cefaclor, cefamandole, cefotaxime, imipenem, enoxacin, ciprofloxacin, roxithromycin, erythromycin, chloramphenicol, and co-trimoxazole, by a microdilution broth method. Cefotaxime, enoxacin and ciprofloxacin with MIC90 and MBC90 of less than 0.03 mg/l) were the most active antimicrobial agents tested. Cefixime, carumonam, aztreonam, and co-trimoxazole (MIC90 and MBC90 less than 0.25 mg/l) showed good activity against most strains. Roxithromycin and erythromycin had limited antibacterial activity (MIC90, 8 and 4 mg/l respectively). There were no chloramphenicol-resistant strains. Five beta-lactamase-negative strains were resistant to ampicillin, cefaclor and cefamandole but susceptible to other beta-lactams tested. Different patterns of tolerance were observed: four of five tolerant strains were tolerant to ampicillin and cefamandole, three to cefixime, cefaclor and cefotaxime, one to aztreonam. One tolerant strain was a beta-lactamase producer. Two other strains were tolerant only to co-trimoxazole.