PEDIATRICS Vol. 117 No. 4 April 2006, pp. e610-e618 (doi:10.1542/peds.2005-1373)
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Severe Pediatric Influenza in California, 2003–2005: Implications for Immunization Recommendations
California Department of Health Services, Richmond, California
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
OBJECTIVE. The 2003–2004 influenza season was marked by both the emergence of a new drift "Fujian" strain of influenza A virus and prominent reports of increased influenza-related deaths in children in the absence of baseline data for comparison. In December 2003, the California Department of Health Services initiated surveillance of children who were hospitalized in California with severe influenza in an attempt to measure its impact and to identify additional preventive measures.
METHODS. From December 2003 to May 2005, surveillance of children who were hospitalized in PICUs or dying in the hospital with laboratory evidence of influenza was performed by hospital infection control practitioners and local public health departments using a standardized case definition and reporting form.
RESULTS. In the 2003–2004 and 2004–2005 influenza seasons, 125 and 35 cases, respectively, of severe influenza in children were identified in California. The mean and median age of cases were 3.1 years and 1.5 years, with breakdown as follows: <6 months, 39 (24%); 6 to 23 months, 53 (33%); 2 to 4 years, 40 (25%); 5 to 11 years, 15 (9%); and 12 to 17 years, 13 (8%). Fifty-three percent (85 of 160) had an underlying medical condition(s), including a neurologic disorder (n = 36), chronic pulmonary disease (n = 26), genetic disorder (n = 19), cardiac disease (n = 18), prematurity (n = 14), immunocompromised status (n = 12), endocrine/renal disease (n = 2), and other (n = 1). Only 16% (15 of 96) of all patients had received influenza vaccination. Thirty-seven patients had an underlying illness that met existing Advisory Committee on Immunization Practices (ACIP) or American Academy of Pediatrics (AAP) recommendations for immunization, but only 8 had been vaccinated.
CONCLUSIONS. More than 3 times as many children were reported to be hospitalized in intensive care with influenza in California during the 2003–2004 season compared with the 2004–2005 season. Because children who are younger than 6 months remain at highest risk for severe influenza yet cannot currently be immunized, development and validation of preventive measures for them (eg, maternal immunization, breastfeeding, immunization of young infants and their close contacts) are urgently needed. ACIP's recent recommendation for influenza vaccination of children with conditions that can compromise respiratory function (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, other neuromuscular disorders) is further supported by the frequency of underlying neurologic disease in these cases of severe influenza. A significant proportion of children with severe influenza in California, including children who are aged 2 to 4 years or have underlying genetic syndromes or prematurity, would not have been routinely recommended for influenza vaccination in 2005–2006 ACIP and AAP recommendations, calling into question whether such guidelines should be expanded. Continued surveillance for severe influenza-related morbidity and mortality is important to measure the impact of influenza on children.
Key Words: influenza • pediatric • intensive care unit • deaths • Fujian • vaccine recommendations
Abbreviations: CDC—Centers for Disease Control and Prevention • ACIP—Advisory Committee on Immunization Practices • AAP—American Academy of Pediatrics
The 2003–2004 Influenza season in the Northern Hemisphere was marked by the emergence of a new drift variant (A/Fujian/411/2002-like [H3N2]; "Fujian") strain of influenza A virus. Reports of pediatric deaths in December 2003 fueled concerns that the new Fujian strain was causing particularly severe disease in children. For the entire 2003–2004 season, 153 influenza-related pediatric deaths were reported by 40 states to the Centers for Disease Control and Prevention (CDC).1 In contrast, the 2004–2005 influenza season was characterized by an increased proportion of disease attributed to influenza B and the emergence of the influenza A/California/7/2004-like (H3N2) "California" strain, which accounted for 78% of influenza A isolates in the United States.2 Only 39 influenza-related pediatric deaths in 17 states were reported to the CDC as of July 6, 2005.2
There is no context for interpretation of these numbers, because reporting of influenza-associated deaths has not been required in many states. Baseline rates of influenza-related morbidity and mortality in children are unknown. Mathematical models have estimated that 92 influenza-associated deaths occurred annually among children who were younger than 5 years between 1990 and 1999.3 Prompted by reports of severe pediatric influenza associated with the emergence of the Fujian strain, in December 2003, the California Department of Health Services initiated enhanced surveillance for children who were hospitalized in PICUs or dying in the hospital with laboratory-confirmed influenza.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
From December 15, 2003, to April 30, 2004, and from October 1, 2004, to April 30, 2005, all 26 hospitals with PICUs and the 61 local public health departments in California were asked to submit a standardized case report form for children who met the following criteria: (1) aged 0 to 17 years; (2) clinical syndrome consistent with influenza or complications of influenza, including lower respiratory tract infection, acute respiratory distress syndrome, apnea, cardiopulmonary arrest, myocarditis, Reye or Reye-like syndrome, or acute central nervous system syndrome; (3) laboratory evidence of influenza; and (4) hospitalization in the PICU or death anywhere in the hospital. NICUs were not surveyed. Hospital infection control practitioners collected data on patient demographics, clinical history, results of testing for influenza and other infections, and hospital course. All laboratory testing was performed as part of the routine hospital evaluation and did not include influenza strain typing. No incentive was offered for collection of information. Infection control practitioners and local health departments were asked to report retrospectively any cases that occurred from October 15 through December 15, 2003.
Statistical Analysis
Statistical analysis was performed with SAS 9.1 using Fisher's exact test.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
A total of 160 cases were reported in California: 125 cases in the 2003–2004 influenza season and 35 cases in the 2004–2005 influenza season. Because surveillance was initiated after the start of the 2003–2004 season, 35 (22%) cases were reported retrospectively. In both seasons, the weeks of peak hospitalizations, December 13 to December 20, 2003, and January 15 to February 12, 2005, respectively, coincided with peaks in influenza-associated outpatient visits and hospitalizations and with rates of laboratory detection of influenza4 (Figs 1 and 2).
|
80 sentinel physicians situated throughout California. Data on the number of laboratory-confirmed influenza virus detections (including rapid antigen detection, isolation, and polymerase chain reaction) are collected weekly from 19 hospital, academic, private, and public health laboratories located throughout California.
|
For both seasons combined, the mean and median ages of patients were 3.1 and 1.5 years, respectively (in the 2003–2004 season: 2.7 and 1.4 years; in the 2004–2005 season: 4.8 and 2.2 years). The age range of patients for both seasons was 1 day to 17.9 years, and the age breakdown was as follows: <6 months, 39 (24%); 6 to 23 months, 53 (33%); 2 to 4 years, 40 (25%); 5 to 11 years, 15 (9%); and 12 to 17 years, 13 (8%; Fig 3). In 2004–2005, there was an increase in the proportion of patients who were older than 5 years compared with the previous year (13% in 2003–2004 vs 34% in 2004–2005; P = .005) and a decrease in the proportion of patients who were 6 to 18 months of age (31% vs 14%; P = .05).
|
The clinical presentations and proportion of patients who required mechanical ventilation were similar for both seasons. The predominant clinical presentations for the 160 patients were symptoms of middle or lower respiratory tract infection (eg, wheezing, stridor, crackles, rales; n = 135 [85%]), febrile seizures (n = 9), sepsis/multiorgan failure (n = 8), fever alone (n = 5), and apnea alone (n = 2). One patient who presented in status epilepticus received a diagnosis of influenza-associated encephalopathy. Sixty-seven percent (91 of 135) of the patients with middle or lower respiratory tract symptoms had radiologic confirmation. Forty-one percent (60 of 147) of patients in this series required mechanical ventilation.
For the 2003–2004 and 2004–2005 seasons, 47% (75 of 160) of patients previously had been healthy, including 52% (68 of 131) of children who were 5 years or younger and 24% (7 of 29) of children who were 6 to 17 years of age. Eighty-five (53%) patients had 1 or more underlying medical conditions, including a neurologic disorder (n = 36), chronic pulmonary disease (n = 26), genetic disorder (n = 19), cardiac disease (n = 18), prematurity (n = 14), immunocompromised status (n = 12), endocrine/renal disease (n = 2), and/or other (n = 1; Table 1, including breakdown by season). Of the 14 patients with a reported history of prematurity, 7 were born at <30 weeks' gestation. The mean and median ages at presentation of these cases with history of prematurity were 1.7 and 0.7 years, respectively (range: 1 month to 1 year, with the exception of 1 patient, who was 15 years of age at time of hospitalization).
|
Results of microbiologic testing identified influenza A in all cases in the 2003–2004 season; in contrast, the 2004–2005 season was marked by a predominance of influenza B (n = 21) over influenza A (n = 13), with 1 influenza detection that was not typed further. For both seasons, a majority of patients (83%; 133 of 160) had their influenza initially diagnosed by rapid antigen detection; the remaining were diagnosed by a combination of isolation (n = 29), immunofluorescence assay (n = 15), polymerase chain reaction (n = 5), serologic testing (n = 1), and unknown (n = 4). Influenza strain typing results for individual cases were not reported. Of the 138 cases of influenza A, the mean and median ages were 2.8 years and 1.5 years, respectively. Sixty-six (44%) patients with influenza A were previously healthy. Of the 21 patients with influenza B, the mean and median ages were 4.6 years and 1.8 years, respectively, and 7 (34%) patients were previously healthy. In both seasons, 4% (6 of 160) of patients also had positive rapid antigen tests for respiratory syncytial virus. Eighteen percent (28 of 160) had evidence of secondary bacterial infection, as suggested by culture of the blood, lower respiratory tract, or pleural fluid (Table 2).
|
Antiviral therapy was provided to 23% (30 of 131) of patients, whose mean and median ages were 3.1 and 1.6 years, respectively (range: 1 month to 18 years). Sixteen (54%) of these patients had underlying medical conditions, including chronic cardiac disease (n = 5), genetic disorder (n = 5), chronic pulmonary disease (n = 4), immunocompromised status (n = 4), neurologic disorder (n = 4), prematurity (n = 2), endocrine/renal disease (n = 1), and other (morbid obesity; n = 1). Twenty-six of these patients presented with a lower respiratory tract illness, 16 required mechanical ventilation, and 6 died.
In the 2003–2004 and 2004–2005 seasons, influenza vaccination status was reported for 86 (69%) and 10 (29%) children, respectively; 13 (15%) of 86 had been immunized at least once in the 2003–2004 influenza season, and 2 (20%) of 10 had been immunized at least once in the 2004–2005 season. No data were available on the number of previous influenza vaccinations. In 2003–2004, 33 (38%) of the 86 children had underlying illnesses that met that season's Advisory Committee on Immunization Practices (ACIP) recommendations for immunization, but only 6 (18%) had been vaccinated. In 2004–2005, 2 (20%) of the 10 children had underlying illnesses that met that season's ACIP recommendations for immunization, and 2 more were aged 6 to 23 months, an age category that was added to ACIP recommendations in 2004–2005; only 2 (50%) of these 4 children had been vaccinated.
A total of 15 deaths were reported through this surveillance system, 7 in the 2003–2004 and 8 in the 2004–2005 seasons. The age breakdown for both seasons combined was as follows: <6 months, n = 2; 6 to 23 months, n = 5; 2 to 4 years, n = 4; 5 to 11 years; n = 2; and 12 to 17 years, n = 2. In both seasons, most patients with a lethal case of influenza presented with lower respiratory tract infection (n = 12), had radiologically confirmed pneumonia (n = 11), and required mechanical ventilation (n = 11). The single patient who received a diagnosis of influenza-associated encephalopathy was not fatal. Whereas 47% of all children who were hospitalized in the PICU were previously healthy, only 4 (27%) of children whose case of influenza was fatal were previously healthy; the remaining had underlying medical conditions (Table 1). Six of the 15 patients whose case of influenza was fatal had evidence of potential secondary bacterial infection (Table 2), 6 received antiviral medication, and 2 had received at least 1 influenza vaccination at least 14 days before onset of symptoms. The number of children who died of influenza at home before being able to receive medical evaluation in the hospital was not determined.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
In this article, we describe results of surveillance for severe pediatric influenza in California in the 2003–2004 and 2004–2005 influenza seasons. More than 3 times as many children were reported to be hospitalized in the PICU with influenza in California during the 2003–2004 season compared with the 2004–2005 season. These observations are similar to national reports of 153 children in 40 states who died of influenza in the 2003–2004 influenza season compared with 39 children in 17 states during the 2004–2005 season.1,2
On the basis of national laboratory data, new antigenic drift variant strains of influenza A (H3N2) were characterized each season: A/Fujian/411/2002-like in 2003–2004 and A/California/7/2004-like in 2004–2005.2 Disease that was caused by influenza B viruses was sporadic in 2003–2004 but accounted for almost one quarter of isolates in the United States in 2004–2005.2 These differences in circulating strains between the 2 seasons may have contributed to the marked difference in the number of cases of severe pediatric influenza reported in California. Although severe influenza seasons that were associated with influenza B have been described, hospitalizations and deaths from influenza are often higher in seasons, such as 2003–2004, when influenza A (H3N2) subtypes predominate.5,6 In addition, the antigenic properties of emerging influenza A strains and their relation to preexisting population immunity may play a role in the seasonal variation in severity. Immunogenicity studies have shown that the 2003–2004 inactivated influenza vaccine that contained influenza A/Panama/2007/99 (H3N2) antigens may have provided little protection against the circulating drift Fujian strain, whose inclusion in the 2004–2005 vaccine provided better protection against the circulating drift California strain.7,8 Additional study is required into the virologic or immunologic mechanisms that might modulate the pathogenicity of different influenza strains.
The age distribution of our patients reported over the 2 years reflects the disproportionate burden of severe influenza in the very young, with >80% being younger than 5 years, more than half of whom were reported as being previously healthy. Influenza illness that required intensive care occurred most frequently in infants who were younger than 6 months, who are too young to be immunized (Fig 3). Prevention of influenza in these young infants is currently limited to vaccination of women during pregnancy or shortly after delivery, which may provide maternal antibody to the fetus and infant; breastfeeding; and vaccination of and promotion of respiratory hygiene to close contacts. Despite the compelling need, there is currently minimal evidence about the efficacy of these interventions.9
One third of cases in our series were 6 to 23 months of age, confirming the vulnerability of these young children for severe influenza-related complications.10,11 In the 2004–2005 influenza season, the ACIP changed the immunization category of 6- to 23-month-old age range from "encouraged" to "recommended."3 As a result, the number of children who were aged 6 to 23 months in the United States and were immunized at least once for influenza increased from 7.4% in the 2003–2004 season to at least 48% in the 2004–2005 season.12 Increased immunization is a possible explanation for why the proportion of patients who were aged 6 to 23 months with severe influenza in our surveillance decreased from 37% in 2003–2004 to 20% in 2004–2005.
One quarter of our patients were aged 2 to 4 years. Estimates of influenza-associated hospitalizations in this age group have ranged from no increased risk to 800/100000 in children with high-risk conditions.10,11 Only 12 (30%) of the 40 children who were aged 2 to 4 years and identified in the combined 2 years of surveillance had an underlying illness for which vaccination was recommended. If national immunization recommendations were to include 2- to 4-year-olds, then almost one fifth of children in this series might have received additional protection against severe influenza.
ACIP and American Academy of Pediatrics (AAP) recommendations advocate vaccinating children with underlying medical conditions that predispose to increased risk for complications from influenza (Table 1).3,13 In our surveillance, more than one quarter of influenza-infected children who were 6 months or older had underlying conditions that were not part of the existing 2003–2005 ACIP or AAP recommendations, most commonly underlying neurologic disease, genetic disorder, and prematurity. These results are consistent with estimates from 2003–2004 national pediatric influenza-related death surveillance data, in which 30 (20%) of 149 patients did not have an ACIP-defined risk factor.14 The importance of neurologic disease as a predisposing risk factor for severe influenza has been suggested by others.15 The underlying mechanisms of vulnerability in the neurologically impaired are unclear but may include inadequate clearance of respiratory tract secretions or susceptibility to recurrent respiratory infection.16 In May 2005, the ACIP added a new risk category to recommendations for influenza vaccination: "any condition (eg, cognitive dysfunction, spinal cord injuries, seizure disorders or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration."17 Our results support this new ACIP recommendation.
Our surveillance also identified a large number of patients with underlying genetic disorders or history of prematurity. In 5 cases, a genetic syndrome was the only reported underlying illness. As part of the genetic disorder, some of these children may have had conditions that otherwise would have qualified them for immunization. For example, it is possible that children with Trisomy 21 may have chronic cardiac, pulmonary, or immunologic disease (eg, immunoglobulin G4 subclass deficiency) that was either undiagnosed or unreported. Likewise, a busy practitioner may find it challenging under current recommendations to categorize quickly whether a child with chronic, multisystem disease should be immunized. Incorporating children with premature birth or genetic conditions into existing immunization recommendations will protect additional children from severe influenza.
Children who are infected with influenza can present with nonspecific symptoms, ranging from lethargy and poor feeding in infants to gastroenteritis and febrile seizures in older age groups, which may not be diagnosed clinically as "classic" influenza. However, the predominant clinical presentation in our surveillance was respiratory illness. Signs and symptoms of influenza-associated encephalopathy were uncommon. In contrast, enhanced surveillance of unexplained pediatric deaths that occurred in Michigan in early 2003 identified 14 cases that were associated with influenza, 8 of which had evidence of influenza-associated encephalopathy.18 Epidemics of influenza-associated encephalopathy in Japan, including 148 cases in the winter of 1998–1999, have occurred in what were otherwise considered to be mild influenza seasons.19,20 The reasons for temporal and regional differences in the syndromic presentation of influenza encephalopathy are unknown but could include differences in genetic susceptibility or local virus strains.
These results should be interpreted with some caution. Because enhanced surveillance was initiated after the 2003–2004 influenza season was under way in response to reports of increasing morbidity and mortality in children, more than one quarter of cases were reported retrospectively, and other, additional early cases may have been missed. Similarly, the number of children with severe influenza without laboratory evidence is unknown. The mortality of reported severe pediatric influenza was higher in 2004–2005 (23%), despite the smaller number of cases in that season, than in 2003–2004 (6%). We speculate whether these fatal cases were missed in the 2003–2004 season because of the late initiation of the surveillance or because press coverage of fatal cases in the first season led to increases in awareness and postmortem testing during the following season. Outcomes other than death were not followed as part of this surveillance. Vaccine scarcity during both seasons may have contributed to low influenza immunization rates in these children.
|
CONCLUSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
We found that a significant proportion of pediatric patients who had influenza and required ICU hospitalization were not recommended to receive vaccination by the existing ACIP and AAP guidelines. Our findings support recent revisions to the ACIP recommendations to vaccinate children with neurologic disorders. Our data suggest, however, that recommendations should be broadened even further to include children who are aged 2 to 4 years or who have genetic disorders and history of prematurity. As children who are younger than 6 months remain at highest risk for severe influenza yet cannot currently be immunized, development and validation of preventive measures for them (eg, maternal immunization, breastfeeding, immunization of young infants and their close contacts) are urgently needed. Continued surveillance for severe influenza-related morbidity and mortality is important to measure the impact of influenza on children and to discover and validate correlates of susceptibility to severe disease.
|
ACKNOWLEDGMENTS |
|---|
This project was supported by the California Department of Health Services, which provided support for design and conduct of the surveillance; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript.
We thank Sandra Jo Hammer and Myan Nguyen for help with design and data entry. We are grateful to Lawrence Walter, John Chapman, and the Kaiser Permanente Division of Research, Kaiser Permanente Medical Care Program (Oakland, CA), for permission to incorporate Northern California Kaiser Permanente inpatient hospitalization data in Figs 1 and 2. Finally, although we cannot name them all, we gratefully acknowledge the contributions of all of the infection control practitioners who work in PICUs throughout California and all of the staff at California local health departments who diligently worked to help acquire the epidemiologic and clinical information and ensured that these cases were reported to the California Department of Health Services.
|
FOOTNOTES |
|---|
Accepted Oct 3, 2005.
Address correspondence to Janice K. Louie, MD, MPH, Viral and Rickettsial Disease Laboratory, California Department of Health Services, 850 Marina Bay Pkwy, Richmond, CA 94804. E-mail: JLouie{at}dhs.ca.gov
The authors have indicated they have no financial relationships relevant to this article to disclose.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
- Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003–2004.
N Engl J Med. 2005;353
:2559
–2567
[Abstract/Free Full Text] - Centers for Disease Control and Prevention. Weekly Report: Influenza Summary Update. Week Ending May 21, 2005—Week 20. Available at: www.cdc.gov/flu/weekly/weeklyarchives2004-2005/04-05summary.htm. Accessed February 21, 2006
- Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB; Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2004;53 :1 –40[Medline]
- California Department of Health Services, Viral and Rickettsial Disease Branch. California Influenza Surveillance Project: 2003–2004 Data and Summary and 2004–2005 Data and Summary. Available at: www.dhs.ca.gov/ps/dcdc/VRDL/html/FLU/Fluintro.htm
- Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States.
JAMA. 2003;289
:179
–186
[Abstract/Free Full Text] - Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States.
JAMA. 2004;292
:1333
–1340
[Abstract/Free Full Text] - World Health Organization. Recommended composition of influenza virus vaccines for use in the 2005–2006 influenza season. Wkly Epidemiol Rec. 2005;80 :71 –75[Medline]
- World Health Organization. Recommended composition of influenza virus vaccines for use in the 2003–2004 influenza season. Wkly Epidemiol Rec. 2003;78 :58 –62[Medline]
- Englund JA. Maternal immunization with inactivated influenza vaccine: rationale and experience. Vaccine. 2003;21 :3460 –3464[CrossRef][Web of Science][Medline]
- Neuzil KM, Mellen BG, Wright PF, Mitchel EF, Griffin MR. Effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children.
N Engl J Med. 2000;342
:225
–231
[Abstract/Free Full Text] - Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children.
N Engl J Med. 2000;342
:232
–239
[Abstract/Free Full Text] - Centers for Disease Control and Prevention (CDC). Estimated influenza vaccination coverage among adults and children: United States, September 1, 2004–January 31, 2005. MMWR Morb Mortal Wkly Rep. 2005;54 :304 –307[Medline]
- American Academy of Pediatrics. Influenza. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003: 388
- Greenberg ME, Wright JG, Murray E, et al. Clinical and Epidemiologic Features of Influenza-Associated Deaths in Children,United States, 2003–2004 Influenza Season. Pediatric Academic Societies' 2004 Annual Meeting; May 15, 2004; San Francisco, CA
- Quach C, Piche-Walker L, Platt R, Moore D. Risk factors associated with severe influenza infections in childhood: implication for vaccine strategy. Pediatrics. 2003;112 (3). Available at: www.pediatrics.org/cgi/content/full/112/3/e197
- Principi N, Esposito S. Pediatric influenza prevention and control. Emerg Infect Dis. 2004;10 :574 –580[Web of Science][Medline]
- Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB; Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54 :1 –40. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5408a1.htm[Medline]
- Centers for Disease Control and Prevention. Severe morbidity and mortality associated with influenza in children and young adults: Michigan, 2003 MMWR Weekly Rep. 2003;52 :837 –840
- Morishima T, Togashi T, Yokota S, et al. Collaborative Study Group on Influenza-Associated Encephalopathy in Japan. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis. 2002;35 :512 –517[CrossRef][Web of Science][Medline]
- Togashi T, Matsuzono Y, Narita M, Morishima T. Influenza-associated acute encephalopathy in Japanese children in 1994–2002. Virus Res. 2004;103 :75 –78[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
