PEDIATRICS Vol. 108 No. 4 October 2001, pp. 1004-1005

COMMENTARY:
Influenza Virus Continues to Pose New Challenges

During a typical influenza season, 20% to 30% of children are infected with influenza virus, with even higher rates during epidemic years. Influenza infection is frequently regarded as a self-limited illness in children. However, 2 recent articles highlight the morbidity associated with pediatric influenza infections in terms of respiratory hospitalizations, outpatient visits, and antibiotic prescriptions.^1-2 In this issue of Pediatrics, Chiu et al³ demonstrate that influenza virus is associated with another significant morbidity in childrenfebrile seizures.

Using a comprehensive surveillance system at Queen Mary Hospital, Hong Kong, Chiu et al³ compared the incidence of febrile seizures among children 6 months to 5 years of age hospitalized with influenza A infections to similar children hospitalized with parainfluenza or adenovirus infections. They reported that among children hospitalized with influenza A infections, 19.5% had febrile seizures. Among children admitted with parainfluenza virus or adenovirus infections, the incidence of febrile seizures was 12.2% and 9%, respectively. Children infected with influenza A virus not only had significantly higher rates of febrile seizures, but they also had higher rates of repeated seizures during the same illness than those infected with parainfluenza virus or adenovirus (odds ratio: 6.7 [95% confidence interval: 2-22.5]).³

Although these results are intriguing, additional studies on the association between influenza A and febrile seizures are warranted. Because the authors limited the study to febrile children infected with influenza A, parainfluenza, or adenovirus, they did not comprehensively examine all children with febrile seizures. Also, we do not know how these results compare with other viral etiologies, including influenza B, human herpesvirus-6, or human herpesvirus-7.⁴ Because the study definitions of influenza A, parainfluenza, and adenovirus infections (culture or rapid antigen) were not clearly stated, it is difficult to assess the potential role of misclassification bias.

Although earlier studies had established a link between influenza infections and seizures, this study has provided the most definitive evidence to date. This retrospective cohort study was possible primarily because the emergency department has had a low threshold for admitting children with acute febrile illnesses and because comprehensive respiratory viral cultures and rapid viral diagnostic studies were routinely obtained on hospitalized children.³ In this hospital, viral testing has been demonstrated to reduce costs by shortening hospital stays and by reducing antibiotic use.⁵ We hope that the investigators will continue to use this large data set to further the understanding of pediatric viral infections. In the meantime, the rest of us will try to promote a similar approach in our medical centers.

What does this report tell us about the pathogenesis of influenza infections? Does the influenza virus have tropism for the central nervous system or does the increased rate of febrile seizures simply reflect the known tendency of influenza to induce high fever? The nearly twofold higher incidence of febrile seizures in children infected with influenza A, as compared with those infected with parainfluenza virus or adenovirus, persisted even after multivariate analysis adjusted for the peak temperature and duration of the fever.³ So, the answer does not seem to lie with the magnitude of the fever.

Several reports of influenza-associated encephalopathy from Japan have suggested that the influenza virus may be targeting the brain. In 1995 Mizuguchi⁶ reported "a new disease entity in Japan that manifested itself as acute encephalopathy after viral infection with influenza A, influenza B, or other viruses". The disorder predominantly affected children between 6 to 18 months of age living in Japan and Taiwan. Since the original description of influenza-associated encephalopathy, many additional cases have been reported.⁷ Most of the described children developed encephalopathy within 2 days of the onset of influenza symptoms, and the first neurologic sign was generalized convulsions. The calculated incidence rate of influenza-associated encephalopathy in Japan has been between 7 and 12.8 cases per 100 000 children.^8,9 Many of the children with influenza-associated encephalopathy either died within a few days of disease onset or had long-term sequelae. The authors emphasized that this disease entity was not Reye's syndrome because the patients with influenza-associated encephalopathy had no history of aspirin intake, had rapid loss of consciousness, and coma ensued within 24 hours. In addition, reports of influenza-associated encephalopathy have indicated that bilateral thalamic lesions are often evident on neuroimaging.¹⁰

Although episodes of acute encephalopathy were reported in the influenza pandemics of 1918 and 1957, these early reports occurred primarily in adults and none manifested neurologic signs within the first 2 days of illness.^11,12 To our knowledge, similar reports of influenza-associated encephalopathy have not appeared in the Western literature. Whether it is unique to Japanese or Taiwanese children or whether genetic, environmental, or other unknown factors are responsible remains a mystery. As noted by Chiu et al,¹³ the recent report of a novel amino acid substitution at the receptor-binding site of the hemagglutinin gene of influenza A that correlates with viral tropism is intriguing. Surveillance for influenza-associated encephalopathy is ongoing in the United States through a large multistate study funded by the Centers for Disease Control and Prevention. Whether this surveillance system will detect cases of influenza-associated encephalopathy remains to be determined.

A practical question remains. Given all of the pediatric influenza-related morbidity, including the reported associations with febrile seizures and encephalopathies, should young children routinely be immunized with the influenza vaccine? This question is hotly debated in the pediatric infectious disease community. In 1998 the Advisory Committee on Immunization Practices formed a working group to explore whether they should recommend annual influenza vaccination for young children without high-risk medical conditions. Recent studies indicate that influenza-attributable hospitalization rates in pediatrics are highest among young children and are comparable with rates seen in other high-risk groups, such as the elderly.^1,2 These findings persisted even after the authors accounted for the cocirculation of respiratory syncytial viruses. Many believe the time has come to recommend routine influenza immunization for all children <5 years of age. Consistent with this position, a decision analysis has predicted that routine influenza immunization of preschool children would be cost-effective.¹⁴

Some warn that the logistics of a wide-scale pediatric influenza immunization program would be too problematic and could not be implemented. For example, only a small percentage of the high-risk children recommended for yearly influenza vaccination actually receive vaccine.¹⁵ However, a number of approaches have increased vaccine coverage levels for other childhood diseases, and for influenza vaccination in high-risk adults. Patient reminder systems, multicomponent educational interventions, standing orders, provider reminder and recall cues, and after-hours clinics for the delivery of vaccines are a few approaches that might be implemented.^16-18 Monitoring immunization rates at the local and national level, and providing feedback to providers is equally important.¹⁶ In a study of children admitted to our pediatric hospital with febrile or respiratory symptoms during the influenza season, parents of high-risk children commonly cited the lack of knowledge or the lack of a physician recommendation for influenza vaccine as the main reason for not vaccinating their children.¹⁹ "An ounce of prevention" still remains preferable to "a pound of cure."

Kathryn M. Edwards, MD
Department of Pediatrics
Vanderbilt University Medical Center
Nashville, TN 37232

Katherine A. Poehling, MD^*
Department of Pediatrics
Vanderbilt University Medical Center
Nashville, TN 37232
^* Quality Scholars Program
Veterans Affairs
Tennessee Valley Healthcare System
Nashville, TN 37212

FOOTNOTES

Received for publication Jun 20, 2001; accepted Jun 20, 2001.

Address correspondence to Kathryn M. Edwards, MD, D-7221 Medical Center North, Department of Pediatrics, Division of Infectious Disease, Vanderbilt University, Nashville, TN 37232. E-mail: kathryn.edwards{at}mcmail.vanderbilt.edu

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