Canadian Adverse Events Following Immunization Surveillance System (CAEFISS): Annual report for vaccines administered in 2012.

BACKGROUND: To describe the adverse event following immunization (AEFI) reporting profile for vaccines administered in Canada during 2012 and surveillance trends relative to reports for vaccines administered from 2005 through 2011. METHODS: Analysis of data based on AEFI reports received by the Public Health Agency of Canada by April 30, 2013, for vaccines marketed in Canada and administered from January 1, 2005, through December 31, 2012. RESULTS: The AEFI reporting rate was 10.1 per 100,000 population in Canada for vaccines administered in 2012 and was inversely proportional to age. There was a trend of declining rates from 2005 (14.8) to 2012 overall and by age group. The vast majority of reports (94%-95%) were non-serious involving reactions at or near the vaccination site, rash and febrile events. CONCLUSION: Canada has a strong pharmacovigilance system for vaccines with one of the highest AEFI reporting rates in developed countries. Vaccines marketed in Canada have a very good safety profile. This report enables comparisons across jurisdictions in Canada and globally.

Canada's Vaccine Vigilance Working Group.

The Vaccine Vigilance Working Group (VVWG) was created in 2004 as part of the National Immunization Strategy to strengthen vaccine safety in Canada. The Group has representation from all federal/provincial/territorial immunization programs across the country, as well as Health Canada regulators and the Immunization Monitoring Program ACTive (IMPACT) network. VVWG works to harmonize vaccine safety monitoring and adverse event reporting and management across Canada by developing and following national guidelines and seeking out best pharmacovigilance practices, including training. It also provides a national vaccine safety sentinel network that uses several mechanisms to rapidly share information on emerging safety issues to enable effective public health response. The "vigilance" in VVWG emphasizes the watchful, ever alert nature and activities of the Group's work. Increased public and health professional awareness of the VVWG's role and activities should help to allay concerns about vaccine safety that lead to vaccine hesitancy and in turn limit the effectiveness of immunization.

The Canadian Immunization Monitoring Program, ACTive (IMPACT): Active surveillance for vaccine adverse events and vaccine-preventable diseases.

For almost 25 years the Canadian Immunization Monitoring Program, ACTive (IMPACT) has been conducting active surveillance for severe adverse events following immunization (AEFIs) and vaccine-preventable diseases in children. The network, which consists of volunteer paediatric infectious diseases investigators at 12 tertiary care paediatric hospitals, is an important component of Canada's AEFI monitoring. The network employs nurses at each of the sites to search for and report possible AEFIs to local, provincial and national public health authorities. The active nature of the surveillance ensures a high level of vigilance for severe AEFIs in children.

An update on respiratory syncytial virus epidemiology: a developed country perspective.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children worldwide, and an important cause of morbidity, hospitalization, and mortality. The infections caused by RSV are seasonal, peaking predictably in the winter months in temperate climates, and in the hottest months and the rainy season in tropical climates. The involvement of the lower respiratory tract, manifest clinically as bronchiolitis or pneumonia, is the hallmark of severe RSV disease. Other indicators of severe disease include requirement for, and duration of, hospitalization, supplemental oxygen, management in an intensive care setting, and mechanical ventilation. Host-related risk factors for severe RSV disease include preterm birth, infection before 6 months of age, chronic lung disease, and congenital heart disease. Environmental risk factors for severe RSV infection include poverty, crowding, exposure to tobacco smoke, and malnutrition. Factors that increase frequency of the infection include young age, multiple gestation, family history of atopy, lack of parental education, household crowding, older school-age siblings, lack of breast feeding, day-care attendance, passive smoke exposure, and discharge from a neonatal intensive care unit between September and December. Recent studies in Europe, North America and Japan have evaluated the number of children affected as well as the medical resources necessary to care for these children. Continuing surveillance is the key to tracking the seasonality, risk factors, morbidity and mortality associated with RSV infection. Epidemiological studies are also the basis for development of appropriate local prevention strategies.

Towards universal childhood immunization against chickenpox?

Live attenuated varicella vaccine is available in Canada. The National Advisory Committee on Immunization recommended immunization of healthy susceptible individuals after one year of age. This was endorsed by a National Varicella Consensus Conference, provided that 90% coverage could be ensured. So far only Prince Edward Island has begun universal childhood immunization. Barriers to achieving high childhood vaccine coverage include: the perception that chickenpox is mild in children but severe in both adults and immunocompromised; concern that vaccine field effectiveness will be much lower than observed in pre-licensure efficacy trials; fear that waning immunity may increase adult cases and the associated disease burden; and uncertainty regarding long term morbidity due to vaccine strain reactivation. In fact, chickenpox is usually an uncomplicated illness in otherwise healthy individuals of all ages. Further, with varicella zoster immunoglobulin (VZIG) prophylaxis and acyclovir treatment soon after rash onset, the course in immunocompromised individuals is also usually benign. However, on a population basis, otherwise healthy children with no identifiable risk factors account for 80% to 90% of all chickenpox-associated hospital admissions and 40% to 60% of case fatalities. A more accurate assessment of the relative merits of varicella immunization should contrast the current natural history of disease (90% to 95% infected symptomatically by age 15 years, 15% lifetime risk of a moderate to severe reactivation episode) with the demonstrated vaccine effectiveness of 70% to 86% against any chickenpox, 95% to 100% against moderate to severe illness and significant reduction of frequency and severity of reactivation illness.

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.

Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial.

CONTEXT: Meningococcal polysaccharide vaccines are not used routinely in infants and toddlers, the groups at highest risk of invasive disease, because of poor immunologic responses to the Neisseria meningitidis serogroup C polysaccharide in these age groups. Meningococcal C conjugate vaccines offer the prospect of circumventing this problem. OBJECTIVE: To assess the immunogenicity and the induction of immunologic memory in toddlers by meningococcal C conjugate vaccine. DESIGN: A multicenter, randomized, observer-blinded controlled trial. SETTING: Urban and suburban family medicine or pediatric practices. PARTICIPANTS: Two hundred eleven healthy toddlers aged 15 to 23 months. INTERVENTION: Two injections at 2 months apart of meningococcal C conjugate (group 1, n = 69), plain meningococcal polysaccharide (group 2, n = 72), or hepatitis B virus vaccine (group 3, n = 70). All toddlers received a follow-up dose of plain meningococcal polysaccharide vaccine 12 months later. MAIN OUTCOME MEASURES: IgG meningococcal C anticapsular antibody concentrations determined by enzyme-linked immunosorbent assay and complement-mediated bactericidal antibody. RESULTS: In group 1, the magnitude of the IgG response to meningococcal C conjugate vaccine was more than 4-fold higher after dose 1 and more than 10-fold higher after dose 2 compared with meningococcal polysaccharide vaccine (group 2) (P<.001). Higher titers persisted in the meningococcal C conjugate group for at least 12 months (P<.001). Group 1, primed with meningococcal C conjugate, had 25-fold higher IgG responses to the meningococcal polysaccharide 1-year booster dose than the controls who had received hepatitis B virus vaccine initially and were given meningococcal polysaccharide vaccine 1 year later for the first time (P<.001). In contrast, group 2, primed with meningococcal polysaccharide, had a 2-fold lower response to the 1-year booster meningococcal polysaccharide dose than the hepatitis B virus control group (P = .006). Serum bactericidal responses paralleled the enzyme-linked immunosorbent assay responses. CONCLUSIONS: Immunization of toddlers with meningococcal C conjugate vaccine induces high titers of anticapsular and bactericidal antibody. Furthermore, this vaccine induces immunologic memory to meningococcal C polysaccharide. In contrast, meningococcal polysaccharide vaccine is less immunogenic than the conjugate vaccine and also induces a hyporesponsive state that persists for at least 12 months.

Age-related immunogenicity of meningococcal polysaccharide vaccine in aboriginal children and adolescents living in a Northern Manitoba reserve community.

OBJECTIVE: To determine the total and functional serogroup C antibody response to a quadrivalent meningococcal polysaccharide vaccine in a group of aboriginal infants, children and adolescents. A secondary objective was to determine their prevalence of meningococcal carriage. DESIGN: Open prospective, before and after intervention study. SUBJECTS: Aboriginal children ages 0.5 to 19.9 years, living in a single Northern community and eligible for a public health immunization campaign conducted in all Manitoba native reserve communities to control a meningococcal serogroup C, electrophoretic type (ET) 15 outbreak. No outbreak cases had occurred in the community at the time of the study. METHODS: Total serogroup C capsular polysaccharide antibody (CPA) and functional bactericidal antibody (BA) responses were measured by enzyme-linked immunosorbent assay and bactericidal assay, respectively. RESULTS: Neisseria meningitidis was recovered from the oropharynx of 13 (5.2%) of 249 aboriginal children including 4 (1.6%) serogroup C isolates, all with the designation C:2a:P1.2,5 ET15. Paired sera from 152 children were available for assay. For CPA the geometric mean concentrations and proportions with > or =2 microg/ml before and after immunization were 0.69, 18% and 12.3, 96%, respectively. A significant increase in serum CPA was achieved by children of all ages, with the greatest response occurring after age 11 years. Among infants < lyear old 89% achieved concentrations of > or =2 microg/ml. For BA the pre- and post-vaccine geometric mean titers were 1.02 and 45.9. The response was significantly associated with age. BA titers > or =1:8 were present, before and after immunization, respectively, in 0 and 0% of infants <1 year old, 0 and 20% of 1- to 1.4-year-olds, 0 and 50% of 1.5- to 1.9-year-olds and 1 and 100% of > or =2-year-olds. CONCLUSION: The age-related total and functional group C meningococcal antibody response after quadrivalent polysaccharide vaccine among aboriginals is similar to that reported for Caucasian children. After age 2 all children made excellent CPA and BA responses. In the younger age groups the BA response was blunted but 82 to 95% achieved CPA titers of > or =2 microg/ml.

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.

Does ribavirin impact on the hospital course of children with respiratory syncytial virus (RSV) infection? An analysis using the pediatric investigators collaborative network on infections in Canada (PICNIC) RSV database.

OBJECTIVES: To determine the relationship between receipt of aerosolized ribavirin and the hospital course of high-risk infants and children with respiratory syncytial virus (RSV) lower respiratory infection (LRI). METHODS: The 1993-1994 Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) RSV database consists of prospectively enrolled children with acute RSV LRI, admitted to nine Canadian pediatric tertiary care centers. After excluding cases with compromised immunity and/or nosocomial infection, subsets with any congenital heart disease (CHD), chronic lung disease (CLD), age .35 (EARLY HYPOXIA) were studied in two ways. First, each risk group subset was analyzed separately to assess the association between ribavirin receipt and measures of disease severity including duration of intensive care, mechanical ventilation, hypoxia and RSV-attributable hospital stay. Secondly, ribavirin was added as an independent variable to a previously described multiple regression model for RSV-attributable length of hospital stay and two mutually exclusive subsets were analyzed: 1) previously healthy patients with >/=1 of: INFANT, PREM, or EARLY HYPOXIA; 2) patients with CHD and/or CLD. RESULTS: Between January 1993 and June 1994, 1425 community-acquired hospitalized cases of RSV LRI were entered into the RSV database. Among these 750 (52.6%) fit into one or more of the defined subsets including 97 CHD, 134 CLD, 213 INFANT, 211 PREM, and 463 EARLY HYPOXIA. The proportion ventilated in each group was 20.6%, 20.9%, 15.5%, 15.2%, and 13.3%, respectively. Across the subsets ribavirin use ranged from 36% to 57% of ventilated patients and 6% to 39% of nonventilated patients. For nonventilated patients in each subset the median RSV-attributable hospital length of stay (RSV-LOS) was 2 to 3 days longer for ribavirin recipients and the duration of hypoxia was significantly increased. Duration of intensive care unit (ICU) stay was also increased for all ribavirin-treated subgroups except those with CHD. In contrast, for ventilated patients, ribavirin therapy was not significantly associated with any of the outcome measures regardless of risk group. In the multiple regression model, ribavirin was significantly associated with a prolonged RSV-LOS both for children with CHD and/or CLD as well as for those whose only risk factors included INFANT, PREM, and/or EARLY HYPOXIA. CONCLUSIONS: These data raise further doubts about the clinical effectiveness of ribavirin in infants and children with risk factors for severe disease. Selection bias, with ribavirin used for sicker children, may have influenced outcome. Nevertheless the long durations of hospitalization, ICU, ventilation, and oxygen supplementation in nonventilated ribavirin recipients stress the need for further randomized trials to assess its efficacy.

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.

Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection.

OBJECTIVE: To provide information on disease attributable to respiratory syncytial viral lower respiratory tract infection (RSV LRI) and to quantify the morbidity associated with various risk factors. DESIGN: Prospective cohort study. SUBJECTS: Patients hospitalized with RSV LRIs at seven centers were eligible for study if they were younger than 2 years of age, or hospitalized patients of any age if they had underlying cardiac or pulmonary disease or immunosuppression. MEASUREMENTS AND RESULTS: Enrolled (n = 689) and eligible but not enrolled (n = 191) patients were similar in age, duration of illness and proportion with underlying illness, use of intensive care, and ventilation. Of the enrolled patients, 156 had underlying illness. The isolates from 353 patients were typeable: 102 isolates were subgroup A, 250 were subgroup B, and one isolated grouped with both antisera. The mean hospital stay attributable to respiratory syncytial virus (RSV) was 7 days; 110 patients were admitted to intensive care units, 63 were supported by mechanical ventilation, and 6 patients died. Regression models were developed for the prediction of three outcomes: RSV-associated hospital duration, intensive care unit admission, and ventilation treatment. In addition to previously described risk factors for an increased morbidity, such as underlying illness, hypoxia, prematurity and young age, three other factors were found to be significantly associated with complicated hospitalization: aboriginal race (defined by maternal race), a history of apnea or respiratory arrest during the acute illness before hospitalization, and pulmonary consolidation as shown on the chest radiograph obtained at admission. The RSV subgroup, family income, and day care attendance were not significantly associated with these outcomes. CONCLUSIONS: Hypoxia on admission, a history of apnea or respiratory arrest, and pulmonary consolidation should be considered in the management of children with RSV LRIs. Vaccine trials should target patients with underlying heart or lung disease or of aboriginal race.