Canada Communicable Disease Report

December 2008

Volume 34

Number 12

Monthly Report

Children hospitalized with Influenza during the 2006-2007 season: A report from the Canadian Immunization Monitoring Program, Active (IMPACT)

C Burton, MD (1), W Vaudry, MD (1), D Moore, MD (2), D Scheifele, MD (3), J Bettinger, PhD (3), S Halperin, MD (4), T Tam, MD (5), B Law, MD (6) for the Canadian Immunization Monitoring Program Active (IMPACT)

1. Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Stollery Children's Hospital, Edmonton, Alberta
2. Infectious Disease Division Montreal Children's Hospital, McGill University Health Centre, Montréal, Québec
3. University of British Columbia, Division of Infectious and Immunological Diseases, Department of Pediatrics, Vancouver, British Columbia
4. IWK Health Centre, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia
5. Centre for Emergency Preparedness and Response, Infectious Disease and Emergency Preparedness Branch, Public Health Agency of Canada, Ottawa, Ontario
6. Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada, Ottawa, Ontario

Introduction

Influenza infection is common among children and is associated with signifi cant morbidity. Although the majority of children with Influenza infection present with respiratory symptoms and fever, Influenza can cause central nervous system (CNS), cardiac, renal or hepatic complications(1-7) . During Influenza season, the rate of hospitalization for cardiorespiratory illness in healthy young children, especially those < 6 months of age, approaches that of high-risk adults(8-10) . The burden of Influenza infection is greatest in the youngest children; recent studies have reported hospitalization rates attributable to laboratory-confi rmed-Influenza in healthy children of 2.5 to 4.5 per 1,000 in children < 6 months of age and 0.9 to 1.2 per 1,000 in those aged 6 to 23 months (11-16) .

Hospitalization rates are higher still in young children with high-risk underlying medical conditions, with estimates of Influenza-associated hospitalization rates of 19 per 1,000 children < 1 year of age and 8 per 1000 children 12 to 35 months of age⁽¹⁷⁾ . The Canadian National Advisory Committee on Immunization (NACI) statement on Influenza vaccination for the 2006-2007 season recommended targeting groups at high risk of serious Influenza infection, including all children aged 6 to 23 months and children with selected chronic medical conditions. As there is no Influenza vaccine currently licensed for children < 6 months of age, NACI recommended immunizing household contacts and pregnant women who are expected to deliver during Influenza season⁽¹⁸⁾ .

The Canadian Immunization Monitoring Program, Active (IMPACT) is a pediatric hospital-based surveillance system that captures information about vaccine-preventable diseases and adverse events after immunization. IMPACT has been carrying out surveillance of children hospitalized for Influenza in Canada since 2003. IMPACT offers an integrated tool for monitoring disease patterns and vaccine programs in Canada by providing real-time case totals supplemented by clinical information. This report summarizes the fourth year of this Influenza surveillance (2006-2007). The goals are to: describe the demographic and clinical characteristics of children hospitalized with Influenza in Canada, document Influenza vaccination status, and identify high risk groups that may not be included in current Influenza immunization recommendations. Comparison with previous years IMPACT data will be reported subsequently.

Methods

Active surveillance for laboratory-confi rmed Influenza admissions amongst 0 to 16 year old children was conducted by the IMPACT surveillance network, whose 12 centres draw referrals from every province and territory and represent over 90% of the pediatric tertiary care beds in Canada. Case patients were admitted to an IMPACT centre with laboratory-confi rmed Influenza infection. Each IMPACT hospital has a policy of routinely testing hospitalized children with respiratory symptoms for viral infection. Children hospitalized with Influenza were identifi ed through virology laboratory reports and/or admission records. Acceptable laboratory evidence of Influenza infection included positive viral culture, immunoassay or nucleic acid molecular testing. Once identifi ed, trained nurse monitors reviewed each patient’s hospital record to determine the reason for admission. Only children admitted because of Influenza or a complication of Influenza were included as case patients. Nosocomial cases were not included.

Demographic information, information about underlying medical conditions, vaccination history, methods of Influenza diagnosis, clinical manifestations, treatment, course in hospital, and outcome data were collected using a standard case report form. Vaccination status was determined by report in the hospital chart or by the vaccine provider. For the analysis, a child ≤ 9 years of age was considered fully vaccinated if they had received two doses for their 1^st Influenza season or one dose for a second season and if the last dose occurred > 28 days before infection. A child > 9 years of age was considered fully vaccinated if they had received one dose during this fl u season > 28 days before infection. Detailed case report forms were completed and submitted monthly to the IMPACT data center in Vancouver, BC. Data were analyzed using SAS v8.1 (SAS Institute, Cary, NC).

Results

A total of 371 children were admitted with Influenza in the 2006-2007 Influenza season. The geographic and temporal distribution of these cases have been previously reported⁽¹⁹⁾ . Peak hospitalizations in eastern and western centers occurred simultaneously. The largest number of cases were reported from the IMPACT centre in Quebec City (n = 90), followed by Montreal (n = 61), Toronto (n = 39), and Vancouver (n = 38) (Table 1).

Table 1. Location of Children Admitted with Influenza by Number and Virus Type

Virus type

Influenza A accounted for 311 (83.8%) cases, and Influenza B for 57 (15.4%) cases. Three children (0.8%) were infected with both Influenza A and B. Peak Influenza A hospitalizations occurred in week 9 (late February/early March) and peak Influenza B hospitalizations occurred in week 14 (mid April). All IMPACT centres reported more cases with Influenza A than Influenza B (Table 1). Influenza B hospitalizations was far higher at the three IMPACT centres in Quebec than at any other Canadian centres. No cases of Influenza B were reported in St. John’s, Halifax, Winnipeg, Saskatoon or Calgary.

The age distribution and demographics of the cases are reported in Table 2. The majority of the hospitalizations occurred in children < 5 years of age (297/371 or 80.1%): 49.5% of cases were < 2 years of age, 30.5% were 2 to 5 years, and 19.9% ≥ 6 years of age. All reported cases of Influenza B occurred in children < 11 years of age. Males accounted for 227 (61.2%) of the admissions.

Table 2. Demographic Characteristics, Virus Type and Vaccination Status by Age of Children Admitted with Influenza, 2006-2007

Previous health status

Of the 371 reported cases, 183 (49.3%) occurred in previously healthy children. The proportion of previously healthy children decreased with increasing age: 56/74(75.7%) < 6 months, 57/110 (51.8%) 6 to 23 months, 53/113 (46.9%) 2 to 5 years, and 17/74 (23.0%) ≥ 6 years were previously healthy (Figure 1).

Figure 1. Health Status by Age Group

The 188 children (50.7%), who were not previously healthy, had a total of 294 chronic medical conditions recorded (Table 3). They included 142 children (75.5%) with conditions for which Influenza immunization was recommended and 46 (24.5%) children with other medical conditions. The most common underlying medical conditions were chronic lung disease in 18.3% of all cases, and neurologic or developmental disorders in 12.4%. Of the 46 children who had an underlying neurologic or developmental condition, 15 had no indication for vaccination, 26 had medical conditions that were vaccine indications, and fi ve had no other medical conditions but were 6 to 23 months of age. Fourteen of the children were considered to have vaccine indications because their neurologic disorders could compromise respiratory functioning, and the remaining 12 children had other high-risk chronic medical conditions. Ten children had isolated developmental delay. Fifteen children had a history of seizures; three of them had simple febrile seizures.

Table 3. Underlying Conditions in Children Admitted with Influenza According to NACI Recommendations for Influenza Vaccination, 2006-2007(18)

Influenza immunization status

At the time of admission 276/371 (74.4%) children were not immunized, 25 (6.7%) had immunizations reported as “up to date” with no further details, and the immunization history of 18 (4.9%) children was unknown. Only 52 (14.0%) children had received the Influenza vaccine and only 37 (10.0%) were fully vaccinated. Of the 15 children who were not fully vaccinated, 12 were < 9 years of age and received one dose of vaccine, and three received the vaccine < 28 days prior to admission. Influenza vaccination was indicated in 207/371 cases; 110 children were 6 to 23 months of age and 97 were > 23 months of age and had a health condition for which Influenza vaccine is recommended. Of these children 32 (15.5%) were fully vaccinated at the time of admission; only 7/110 (6%) of all children aged 6 to 23 months were vaccinated appropriately, two of whom were previously healthy. Reasons for not vaccinating were given for 134 cases and the most common reasons were: age exclusion (n = 74), being unaware of vaccine indication (n = 24), being too ill (n = 12), and parental refusal (n = 8). Other reasons included being counseled against immunization by a health care provider (n = 4) and lack of vaccine availability (n = 2).

Clinical presentation

Fever and cough were the most common clinical manifestations, present in 88.7% (329/371) and 79.5% (295/371) of cases respectively. Other symptoms included respiratory distress (n = 155), wheezing (n = 69), pneumonia (n = 63), croup (n = 12), and apnea (n = 6). Many children also had diarrhea, vomiting, or dehydration (n = 139). Otitis media was reported in nine cases. Few children presented with myositis (n = 8), and those who did were infected with Influenza B.

Neurologic manifestations included seizures (n = 34), encephalitis (n = 6), and aseptic meningitis (n = 1). Of the 34 children presenting with seizures, 32 (94.1%) were between the ages of 6 months and 5 years of age, and 16 (47.1%) had underlying neurologic or developmental conditions. Other severe manifestations included one case of myocarditis, and four cases of hepatitis.

The hospital course for children admitted with Influenza is summarized in Tables 4, 5 and 6. The overall median hospital stay was 3 days; the shortest median stay was among children < 6 six months of age (2 days) and the longest among children > 12 years of age (6 days). Children, who were previously healthy, had only conditions for which the Influenza vaccine was not indicated, and those with underlying conditions, which were indications for the Influenza vaccine, had median length of stays of 2, 3.5, and 4.5 days respectively.

Table 4. Vaccination Status and Hospital Course of Children Admitted with Influenza by Health Status, 2006-2007

Table 5. Hospital Course of Children Admitted with Influenza by Age, 2006-2007

Table 6. Hospital Course of Children with Underlying Neurologic or Developmental Conditions Admitted with Influenza by Age, 2006-2007

Bacterial complications

There were 27 cases with laboratory-confi rmed bacterial infections; three of the cases had two documented bacterial infections. Urinary tract infections were the most common documented bacterial infections (n = 9), and Escherichia coli was the most commonly isolated organism (n = 6). There were six episodes of bacteremia, two bacterial pneumonias, one empyema, three cases of pharyngitis, three cases of tracheitis, and one each of cellulitis, diarrhea, otitis media and sinusitis. There were two cases of meningitis, one with Neisseria meningitidis and the other with Klebsiella pneumoniae. There was one Staphylococcus aureus infection and two infections with Streptococcus pneumoniae. Antibiotics were used in 73.0% of cases (271/371). They were used with equal frequency in previously healthy children and children with underlying medical conditions (odds ratio = 0.96, 95% confi dence intervals 0.6 to 1.6). Thirty (8%) children were treated with oseltamivir; no other antivirals were used.

Intensive hospital care

A total of 42 (11.3%) children required ICU admission; nearly half of them (n = 20) were previously healthy. Of the 22 children who were not previously healthy, nine (40.9%) had underlying neurologic or developmental conditions. The proportion of children requiring ICU admission was highest in the 2 to 5 year age group (17/113 or 15.0%), followed by the 6 to 23 month age group (13/110, 11.8%). Intubation and assisted ventilation were required in 20 (5.4%) children. The majority of intubations occurred in children 2 to 5 years of age (n = 9), followed by children 6 to 23 months (n = 7). A slightly higher proportion of intubated children had underlying medical conditions (12/20, 60.0%). Forty-fi ve percent (9/20) of children requiring mechanical ventilation presented with seizures. Bacterial infections were only documented in 5/42 children admitted to ICU, three of whom were intubated. One child required extracorporeal membrane oxygenation.

Mortality

There were two deaths. Case A was a 5 year old previously healthy female who presented with fever, gastrointestinal symptoms, and encephalitis. Influenza A was isolated and subgroup analysis revealed that it was an H1N1 strain. She had not received the Influenza vaccine. She was admitted to the ICU and ventilated and she was treated with antibiotics but not antivirals. She died 2 days after admission. Case B was a 5 year old male with multiple chronic medical problems, including chronic lung disease, hypoxic ischemic encephalopathy, a seizure disorder and short gut secondary to intestinal perforation. He presented with fever, cough, respiratory distress and seizures. Influenza B was isolated. He had been fully vaccinated prior to admission. He spent a total of 4 days in the hospital, 2 of which were in the ICU, and he required ventilation. He was treated with antibiotics but not with antivirals. No bacterial infections were documented in either case.

All other children recovered from their infections and were discharged home. Long-term sequelae were anticipated in fi ve children: three of whom were previously healthy, one who had chronic lung disease, and one who was born at 32 weeks gestation and 41 weeks corrected age at admission. All of the children with sequelae were < 3 years of age at admission, and none were immunized. Bacterial infections were documented in two of the children, and one child was diagnosed with nephrotic syndrome during his admission. Three of the children had ICU stays, two of whom presented with seizures.

Discussion

Influenza infection is the most common vaccine-preventable illness among Canadian children. IMPACT captures the circulating Influenza type (A vs. B), the age profi le of hospitalized patients and the spectrum of clinical manifestations and severity of Influenza infection in hospitalized children. IMPACT also facilitates identifi cation of high-risk groups to target in future immunization programs.

Influenza A accounted for 83.8% of pediatric Influenzarelated hospitalizations this season. The 2- to 5-year age group was the predominant age group (30.5%) admitted to hospital in Canada followed closely by the 6 to 23 month age group (29.6%). The recommendation to immunize all children age 6 to 23 months was introduced in the 2004-2005 season. The median duration of hospital stay was 3 days and was shortest for the youngest children and those without underlying medical conditions. The proportion of children admitted to ICU was 11.3% and included some previously healthy children.

The extensive antibiotic use (66.7%) likely results from diffi culties distinguishing viral versus bacterial causes of symptomatology, especially in young children. Reasons for the limited use of oseltamivir (6.5%) may include delayed diagnosis of Influenza, presentation late in infection, and rapid improvement of symptoms without treatment. Oral oseltamivir, when given < 48 hours after onset of symptoms, has been shown to be effective in decreasing duration of symptoms in Influenza infection in children ≥ 1 year of age, but evidence for it’s use in younger children and in hospitalized patients is limited^(20,21) .

pneumococcal infections, but in our series, documented bacterial infections were rare^(4,6,22) . In the 2006-2007 season there was one child with S. pneumoniae bacteremia and one child with laryngotracheitis who had both S. pneumoniae and S. aureus isolated from tracheal aspirates. We recognize that bacterial infections were likely under-reported, as laboratoryconfi rmation of bacterial etiology requires invasive procedures, which may not be performed in children prior to the initiation of antibiotic therapy.

Although vaccination is the most effective way of preventing or attenuating Influenza infection in individuals at high-risk of Influenza-related complications, vaccination rates remain low⁽¹⁸⁾ . Both the inactivated and the live Influenza vaccine have been shown to be safe and effective in children > 2 years of age, but less data are available for children < 2 years of age^(23-27) . The proportion of children with vaccine indications, who are effectively vaccinated at the time of admission, was quite low at 32/207 (15.5%). It is possible that fully vaccinated children are underrepresented in the hospitalized population because they are protected against severe infection and hospitalization. Given the burden of Influenza infection in this age group and the current vaccine recommendations, more research into the safety and efficacy of Influenza vaccines in children < 2 years of age is warranted.

Neurologic and developmental disorders are the second most frequently identifi ed underlying medical conditions among children admitted to IMPACT centres. The burden of Influenza in children with neurologic and neuromuscular disease has been described in other studies and these conditions have been identifi ed as risk factors for: respiratory failure, prolonged hospital stay, and Influenza-related neurologic complications^{(11,12,28,29)} . One of the two deaths reported by IMPACT this year was in a child with underlying neurologic illness. This mirrors the fi ndings from the 2003- 2004 Influenza season in the United States where neurologic or neuromuscular conditions were identifi ed in one third of the 153 Influenza-related deaths⁽⁶⁾ .

Influenza is also an important cause of febrile seizures in previously healthy children, and in children with a history of febrile seizures. Children who develop febrile seizures with Influenza infection may be more likely to be admitted to hospital, as some studies have found they are more prone to atypical febrile seizures^(7,30) . In our series, 34 children presented with seizures in the 2006-2007 season, and nine of them required mechanical ventilation. In Canada and in the United States, children with neurologic or developmental conditions are not specifi cally recognized as a highrisk group for whom Influenza vaccination is routinely recommended, unless their conditions are considered to compromise the management of respiratory secretions and are associated with an increased risk of aspiration^(18,32) . Of the 46 children admitted in the 2006-2007 season with an underlying neurologic or developmental condition, 15 had no indication for vaccination, and 10 had isolated developmental delay. Expansion of the current Influenza immunization guidelines to include children with neurologic or developmental conditions, including those with a history of febrile seizures and isolated developmental delay, might be beneficial.

There were some limitations to our study. The data presented likely underestimate the impact of hospitalization for Influenza as children admitted with unusual manifestations or late complications of Influenza may not have been tested or may have had negative results.

Testing practices vary between centers, and children presenting with fever without respiratory illness may not have been consistently tested. It is possible that the burden of Influenza disease is overestimated in infants, especially those < 6 months of age, as infants presenting with fever are more likely to be tested for viruses than older children and more likely to be admitted to hospital with less severe disease. Another limitation of the study was the lack of population data to enable the calculation of age-specifi c incidence rates of hospitalization for Influenza. Challenges in documenting vaccination status arise from inadequate documentation of immunization history (e.g. Up To Date only). Documentation of complete vaccine histories, including Influenza vaccine history where appropriate, should be encouraged both to improve data collection about vaccination status and also to provide an opportunity for health-care providers to discuss indications for Influenza vaccination with parents.

Conclusions

Influenza infections continue to represent a signifi cant health burden among children in Canada, especially among children < 5 years of age and those with high-risk underlying medical conditions. Children with neurologic and developmental disorders appear to be at risk of severe Influenza infections and Influenza-related complications and should be identified as such and targeted in future Influenza immunization programs. Continued active prospective hospital-based surveillance through IMPACT will be important to monitor disease patterns and effects of Influenza vaccine programs in Canada.

Acknowledgements

We thank the IMPACT nurse monitors, nurse liaison, and the data centre staff. Special thanks for statistical analysis to S. Fan, Department of Pediatrics, Vaccine Evaluation Center, University of British Columbia, Vancouver. Funding for this project was provided by the Public Health Agency of Canada. The IMPACT network is administered by the Canadian Pediatric Society.

IMPACT Participants

IMPACT investigators and participating centres include the following: Dr. S. Halperin (IWK Health Centre, Halifax, Nova Scotia); Dr. R. Morris (Dr. Charles A. Janeway Child Health Centre, St. John’s, Newfoundland); Dr. P. Déry (Centre mère-enfant de Québec, Ste-Foy, Quebec); Dr. M. Lebel (Hôpital Sainte-Justine, Montréal, Quebec); Dr. D. Moore (Montreal Children’s Hospital, Quebec): Dr. N. Le Saux (Children’s Hospital of Eastern Ontario, Ottawa, Ontario);Dr. D. Tran (Hospital for Sick Children, Toronto, Ontario); Dr. J. Embree (Winnipeg Children’s Hospital, Manitoba); Dr. B. Tan (Royal University Hospital, Saskatoon, Saskatchewan); Dr. T. Jadavji (Alberta Children’s Hospital, Calgary, Alberta); Dr. W. Vaudry (Stollery Children’s Hospital, Edmonton, Alberta); Dr. D. Scheifele, Dr. J. Bettinger (British Columbia Children’s Hospital, Vancouver, British Columbia).

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