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COMMENTARY |
Division of Pediatric Infectious Disease
New England Medical Center
Tufts University School of Medicine
Boston, MA 02111
Department of Pediatrics
University of Maryland
Baltimore, MD 21201
Abbreviations: RSV, respiratory syncytial virus • PIV, parainfluenza virus • SARS, severe acute respiratory syndrome • NVSN, New Vaccine Surveillance Network
Recent years have witnessed a dramatic surge in understanding of viral upper and lower respiratory tract disease in children (Table 1). The epidemiology of established viral pathogens (eg, respiratory syncytial virus [RSV] and parainfluenza viruses [PIVs]) continues to be clarified, and new pathogens have been identified (eg, human metapneumoviruses and the coronavirus that causes severe acute respiratory syndrome [SARS]). Although the relentless emergence of antigenic variation among influenza viruses continues, progress is being made to prevent or control disease in children caused by this virus through active immunoprophylaxis (trivalent inactivated vaccine, live attenuated vaccine) and new antiviral agents (neuraminidase inhibitors). Development of any new viral vaccine, antibody for immunoprophylaxis, or antiviral drug is a tedious and expensive proposition. To identify which interventions will have the greatest societal benefit and utilize interventions in the most cost-effective fashion, reliable estimates of rates of disease must be known. A report in this issue of Pediatrics1 describes the results from 1 year of the New Vaccine Surveillance Network (NVSN), an important new program sponsored by the Centers for Disease Control and Prevention. This project initiates a surveillance network to prospectively establish yearly hospitalization rates at sentinel hospitals in Nashville, Tennessee, and Rochester, New York, for acute viral respiratory illness in children <5 years old.
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Influenza is recognized widely to be a major cause of respiratory morbidity in young healthy children, particularly among those <24 months old.7 During the first year of the study by Iwane et al,1an influenza-associated hospitalization rate of 1.7 per 1000 children <12 months old was found, a figure that is approximately one eighth the hospitalization rate due to RSV and approximately one half the hospitalization rate due to PIVs in similarly aged infants. Hospitalization rates due to influenza vary among studies in different years depending on the virulence of the circulating strain and the correlation between vaccine strains and those circulating in the community, but the rates found in this active surveillance study are similar to those reported elsewhere.7–10 The demonstration that 80% of influenza-associated hospitalizations occurred in children <2 years old emphasizes the importance of the recent recommendation by the American Academy of Pediatrics and the Advisory Committee for Immunization Practices for universal immunization of all children 6 to 24 months old starting in the fall of 2004.7 The influenza vaccine is the first vaccine for children that will require administration on a yearly basis. For children <9 years old with no previous influenza vaccination, 2 doses should be administered before December, which presents a challenge because influenza vaccines generally do not become available before late September or October. This significant change in the immunization schedule is based to a large extent on the fact that hospitalization rates due to influenza among children <24 months old exceed influenza-induced hospitalization rates in healthy adults >50 years old, a group for whom yearly vaccination has been recommended for some time.
Despite the predictability with which influenza strikes each year, nuances are common from one season to another. The 2003–2004 influenza season was unusual for several reasons. First, onset of influenza was early, with the percentage of deaths caused by pneumonia and influenza crossing the epidemic threshold in November and resulting in peak activity in December.11 Usually, influenza activity begins in November, peaks in January or February, and wanes in April. Early onset of disease complicates efforts to vaccinate large numbers of children and adults prior to onset of the season. Second, during the 2003-2004 season, vaccine strains did not fully correspond to strains circulating in the community. Approximately 80% of influenza A(H3N2) isolates were A/Fujian/411/2002(H3N2), a stain that is antigenically distinct from the corresponding vaccine strain A/Panama/2007/99(H3N2).11 The effectiveness of the immune response to the Panama strain contained in the vaccine against laboratory-confirmed influenza caused by the Fujian strain is not yet determined. However, at least some degree of cross protection is highly likely. Third, concern caused by early reports of severe complications occurring in previously healthy children contributed to heightened demand for vaccine and subsequent shortages. As of February 2004, 135 influenza-associated deaths in persons <18 years old (mean age: 3 years) were reported to the Centers for Disease Control and Prevention from 33 states. Among 76 of these children whose vaccination status was known, only 3 had been vaccinated adequately against influenza, although 32 were in a high-risk category. In addition, influenza-associated acute necrotizing encephalopathy, a widely recognized disease of young children in Japan, has recently been described in the United States.12 Fourth, this was the first year that an intranasal, cold-adapted, temperature-sensitive, live attenuated influenza vaccine was commercially available for immunization of non-high-risk persons between 5 and 49 years old. Although this vaccine comprised only 1 million of the 
85 million doses distributed during the 2003–2004 season, experience regarding safety and efficacy was acquired and seems to be consistent with prelicensure studies. There is some evidence that live attenuated influenza vaccine may offer an advantage over the killed vaccine against drifted strains, although this requires additional confirmation. Fifth, outbreaks of avian influenza A (H5N1) occurred in poultry flocks in several Asian countries during 2003–2004. Twenty-two deaths occurred among 32 human cases because of this strain. Human cases are presumed to have occurred from contact with saliva, nasal secretions, or feces from infected birds. Because the H5N1 strain has not acquired genes from human influenza viruses, person-to-person spread seems to be inefficient at the present time. Of additional concern, the Asian H5N1 strain is resistant to amantadine and rimantadine, although susceptibility to oseltamivir and zanamivir is retained. Outbreaks of avian influenza strain H7N2 occurred among some poultry flocks in the United States, but this second avian strain does not generally infect humans. If either avian strain acquires the capacity for efficient person-to-person transmission, worldwide pandemics will be likely. Confirmed influenza illness, hospitalization, complications, and deaths among children are not reportable conditions, so comparison with earlier years is not available. Results from the NVSN program will complement other surveillance programs in addressing each of these issues and providing an early warning to threatening changes in influenza epidemiology.
Human metapneumoviruses were first identified as a cause of respiratory tract disease in 2001.13 Retrospective studies of stored nasopharyngeal aspirate specimens from young children with bronchiolitis and pneumonia of unknown etiology suggest that this agent may cause 10% of all hospitalizations due to lower respiratory tract disease.14 The spectrum of disease and the epidemiology of this RNA virus seem to closely resemble those of RSV. No vaccine is available, and if vaccine development proves to be problematic, disease prevention in certain high-risk populations with passively administered antibody is a possibility. In the study by Iwane et al,1 36% of hospital admissions were due to either human metapneumoviruses or picornaviruses (enteroviruses or rhinoviruses). The overall prevalence of human metapneumovirus infection, including the impact of this virus on high-risk infants, needs to be defined carefully with prospective studies, but findings to date suggest that this virus may cause hospitalization in young children at a rate that is second only to RSV.15 Oftentimes the microbial etiology of acute respiratory tract disease in hospitalized children remains undetermined despite careful analysis of respiratory specimens. In the surveillance study by Iwane et al, no detectable virus was found in 39% of children <5 years old who were hospitalized for febrile or acute respiratory illness.1 Because both viral culture and polymerase chain-reaction assays were used for identification of viruses from nasal and throat specimens, it is unlikely that viruses were not detected because of insufficient sensitivity of the assay. It is more likely that many of these illnesses were caused by undiscovered respiratory pathogens.
It can be predicted that entirely new viral respiratory diseases will continue to emerge, that previously unrecognized viruses will be identified by using new techniques, and that known viruses will continue to mutate. Coronaviruses are known to cause a common-cold syndrome with symptoms similar to those caused by rhinovirus infection. In November 2002, the first reports of an atypical pneumonia were issued from the Guangdong province in China, and in <1 year, >8000 patients (mostly adults) from 26 countries were diagnosed with SARS. Within months the etiologic agent of SARS was determined to be a coronavirus (SARS-CoV), a virus that is now known to circulate in animals, particularly Himalayan palm civets.16 Seroepidemiologic data suggest that SARS-CoV did not infect humans previously. This virus crossed the species barrier, moving from animals to humans, and provides a dramatic example of the sudden appearance of a new respiratory virus. Perhaps the greatest capacity for widespread disease and social disruption will come from new strains of influenza viruses that acquire the capacity to move between species, from water foul to humans, because of natural evolution or an act of bioterrorism with an intentionally altered strain.
Respiratory infections caused by RNA viruses will continue to challenge our ability to prevent and control outbreaks of disease. To address the growing public health threat posed by respiratory viruses in the coming years, surveillance will be essential for establishing public health policy and directing federal and industry-sponsored research efforts. Firmly establishing population-based incidence rates is a step on the road to development of new vaccines and novel antiviral agents. Results from the NVSN should offer vital information regarding respiratory pathogens of children and adults that we know for certain will appear.
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FOOTNOTES |
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Address correspondence to H. Cody Meissner, MD, Pediatric Infectious Disease Division, Tufts-New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail: cmeissner{at}tufts-nemc.org
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REFERENCES |
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 TOP REFERENCES |
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This article has been cited by other articles:
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  F. T. Bourgeois, C. Valim, J. C. Wei, A. J. McAdam, and K. D. Mandl Influenza and Other Respiratory Virus-Related Emergency Department Visits Among Young Children Pediatrics, July 1, 2006; 118(1): e1 - e8. [Abstract] [Full Text] [PDF]
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S. S. Mou, T. A. Nakagawa, E. C. Riemer, T. W. McLean, M. H. Hines, and A. K. Shetty Hemophagocytic Lymphohistiocytosis Complicating Influenza A Infection Pediatrics, July 1, 2006; 118(1): e216 - e219. [Abstract] [Full Text] [PDF]
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