A novel H1N1 influenza virus has emerged from swine and is causing a worldwide pandemic. Children and young adults have been most affected, in terms of both numbers of cases and severity of disease. Perhaps the most striking feature of the pandemic so far is that fewer than half of those hospitalized or killed by this virus have had identifiable prior medical conditions or risk factors.
A novel H1N1 influenza virus has emerged from swine and is causing a worldwide pandemic. Children and young adults have been most affected, both in terms of numbers of cases and severity of disease. Perhaps the most striking feature of the pandemic so far is that fewer than half of those hospitalized or killed by this virus have had identifiable prior medical conditions or risk factors. Diagnostic and treatment options for infections with the H1N1 swine-origin influenza virus (S-OIV) continue to change as the pandemic progresses. H1N1 S-OIV is resistant to the adamantanes, but it is sensitive to neuraminidase inhibitors. Preparations for production and distribution of a vaccine against the H1N1 S-OIV are under way, but the vaccine's efficacy and the timing of its availability in relation to the peak of the pandemic remain uncertain.
Key words: Influenza virus • Pandemic • Children • Pneumonia • H1N1
After more than 40 years of preparation, the world is now confronting a new pandemic. A novel H1N1 influenza virus has emerged from an animal reservoir and is spreading globally.1 As expected, the clinical attack rate is highest in children, and children and young adults of school age are acting as the main vectors of transmission.2 Surprisingly, however, much of the severe disease that is occurring with this new pandemic strain is also manifesting in school-age children and young adults, groups that are typically spared the most serious outcomes during seasonal influenza.1,3 As winter returns to the Northern Hemisphere, the tempo and severity of the pandemic are expected to increase.
One of the surprises of this nascent pandemic is that an old version of a common subtype, H1N1, has returned, rather than a new subtype, such as the H5N1 viruses circulating in Eurasia and Africa, emerging.4 Although the virus appears to be a strain of mixed ancestry that emerged from the pig reservoir, the gene encoding the most critical protein for infection and immunity, the hemagglutinin, is a descendant of a similar gene from the 1918 pandemic strain. An H1N1 virus derived from the wild bird reservoir is believed to have entered both humans and pigs in 1918, causing severe disease in both.5 The two viruses adapted in each host, diverging from each other, with the swine version reaching evolutionary stasis in the 1930s.
In recent decades, however, this “classic” swine strain began to “reassort” (mix and match its genes) with other human and bird viruses, creating a series of hybrid viruses.6 The H1N1 pandemic strain is one of these newly emerged viruses, and it contains genes derived from human viruses, North American and Southeast Asian pig viruses, and avian viruses.
In the first 4 months of the pandemic, more than 134,000 cases had been confirmed in certified laboratories and more than 800 persons had died.7 At that point, the World Health Organization declared that the pandemic had spread worldwide and stopped collecting case ascertainment data from affected countries. On the basis of data from North America, Chile, the United Kingdom, and Japan, the median age of infected persons appears to be 12 to 19 years, and the most severe disease is occurring in persons in this age-group or in those who are slightly older.1-3,8-10 Some of the age distribution may be explained by the high social contact rate among this age-group and clustering in schools, but immunological factors are likely in play as well.
Although infection with or vaccination against recent seasonal H1N1 viruses does not appear to provide protection against the H1N1 swine-origin influenza virus (S-OIV), viruses that were antigenically similar circulated between 1918 and 1947, and persons older than 60 years have some circulating antibodies that recognize the new pandemic strain.11
The clinical manifestations of influenza differ by patient age and by viral strain. The presenting triad of cough, fever, and myalgias is typical of disease in adults and may be accompanied by ancillary symptoms, such as headache, sore throat, and rhinorrhea (Table 1).
Children, particularly infants, are more likely to present with GI symptoms, such as vomiting and diarrhea, and cough and myalgias are often less prominent findings. The limited clinical information available on the H1N1 S-OIV has focused mainly on severe cases, but it suggests that the presentation is similar to that of influenza in adults, with perhaps a higher frequency of vomiting and diarrhea.
Complications of influenza include otitis media, viral pneumonia, secondary bacterial pneumonia, and encephalopathy. Particularly concerning in recent years has been the emergence of methicillin-resistant Staphylococcus aureus as a cause of necrotizing pneumonia in children with influenza.12 Although secondary bacterial pneumonia was the most common cause of death in previous pandemics, it has not been a prominent feature of the current pandemic.13,14 Most deaths have resulted from viral pneumonia.3
Influenza-associated encephalopathy is a recognized but uncommon complication of influenza that is almost exclusively seen in young children who have never been vaccinated against influenza.15,16 This clinical manifestation has been associated with the H1N1 S-OIV, although-interestingly-in older children between 7 and 17 years of age.17
Some of the risk factors for severe disease from H1N1 S-OIV are similar to those for seasonal influenza, such as immunosuppression, pregnancy, and chronic medical conditions (including cardiopulmonary disease). Persons at both extremes of the age range, infants and the elderly, have not experienced more severe disease, as is common with seasonal influenza, but initial reports have linked obesity to an increased risk of poor outcomes.9 Obesity has not been previously recognized as a risk factor for hospitalization from seasonal influenza. Perhaps the most striking feature of the pandemic so far is that fewer than half of those hospitalized or killed by this virus have had identifiable prior medical conditions or other risk factors to explain these outcomes.
Vaccines against influenza
Influenza vaccination is currently recommended for all children aged 6 months to 18 years.18 The reasoning behind this recommendation is 2-fold: children experience significant morbidity and some mortality from influenza, and they also are the main vectors for transmission and spread of the virus.19 Reduction in this pool of infected children should provide a benefit to those who are at highest risk for severe outcomes from influenza-an important consideration, since the vaccine is often less effective in these persons-and prevention of exposure may provide a larger public health benefit than attempted immunization. Because much of the severe disease attributed to influenza stems from secondary bacterial complications, provision of pneumococcal vaccine to at-risk groups, including children and the elderly, should also reduce the frequency and severity of disease.20
Preparations for production and distribution of a vaccine against the H1N1 S-OIV are under way. The first doses are now available. A single dose of the H1N1 pandemic vaccine is being recommended for adults 18 years and older. It is not yet clear whether all persons younger than 18 will require 2 doses of vaccine or whether an intermediate cutoff age, such as 9 years, can be established as is done for seasonal influenza immunization.
Supply is likely to be uneven in many parts of the country because of differences in distribution and demand, which would cause delays in administration. Because the pandemic virus is already in wide circulation and has continued to cause outbreaks throughout the summer, vaccinating those most in need before the peak of the pandemic is likely to present a significant challenge.
Efforts have been made to prioritize the order of vaccination in the event that a limited number of persons can be vaccinated or distribution is staggered over time.21,22 On the basis of the early epidemiology, the highest priority is likely to be given to pregnant women, children and young adults through age 24 years, persons with chronic medical problems or immunocompromise who are aged 25 to 64 years, and contacts of infants younger than 6 months.
In addition, health care workers and emergency services personnel are likely to be vaccinated in the early stages of distribution, since they will be caring for those affected. Elderly persons, who are typically a major risk group targeted in seasonal influenza vaccine campaigns, are unlikely to receive high priority for vaccination because of their low case attack rate in the early stages of the pandemic.
Antiviral prophylaxis and treatment
Two classes of antivirals are licensed for the prevention or treatment of influenza (Table 2).
The adamantanes, including amantadine and rimantadine, target the function of the virus M2 ion channel during an early stage in the virus life cycle, aborting infection. They have been shown to be effective for both prophylaxis of infection and treatment of symptoms, but they have adverse effects, including CNS disturbances, that limit their use.23 Resistance develops readily to these drugs, and H3N2 subtype influenza viruses circulating in 2008-2009 were uniformly resistant.24 Although seasonal H1N1 subtype viruses were mostly susceptible to the adamantanes last year, the H1N1 S-OIV strain is resistant, and these drugs are not currently recommended for use.25
The second class of antivirals target the neuraminidase protein of influenza viruses, preventing budding and escape of newly produced viruses.26 Because these drugs prevent cell-to-cell spread, but not infection and death of individual cells, it is important to begin therapy as soon as possible before dissemination of virus throughout the respiratory tract. The 2 licensed neuraminidase inhibitors, oseltamivir and zanami-vir, both are effective for prophylaxis and treatment of infection. In healthy adults, neuraminidase inhibitors have been shown to reduce the duration of influenza symptoms by 1 to 2 days and to prevent complications, such as otitis media, viral pneumonia, and secondary bacterial pneumonia.27-29
Importantly, the effects on resolution of symptoms and the recommended duration of therapy (5 days) are based on the results of studies in healthy persons with mild disease. It is not clear whether the dose, duration of therapy, and expectation of benefit should be the same in immunocompromised patients or in patients who have severe or complex disease manifestations.
The newly emergent H1N1 S-OIV is resistant to the adamantanes and susceptible to neuraminidase inhibitors. Oseltamivir has been widely used for both treatment and prophylaxis of close contacts during the current pandemic. Several instances of emergence of resistance to oseltamivir under drug pressure have been documented, although the strains involved remained susceptible to zanamivir, and further transmission of the resistant strains was not documented.30
The best treatment for encephalopathy resulting from H1N1 S-OIV infection is uncertain, as is the pathogenesis of this manifestation of influenza. If viral replication in the brain is involved, effective antiviral treatment may not be possible, since neuraminidase inhibitors do not cross the blood-brain barrier (as do the adamantanes), and resistance to the adamantanes precludes their use.31 Reduction of virus titer in the lung with a neuraminidase inhibitor and supportive care may be the best available options.
In outpatient settings, the diagnosis of influenza is typically based on clinical grounds in the context of awareness of circulation of the virus. Antigen-based detection methods are used in some clinics, but these have poor sensitivity for both seasonal influenza and H1N1 S-OIV infection (the sensitivity is about 50%, but specificity is 99%, compared with reverse-transcription polymerase chain reaction [PCR]).32 PCR-based assays are available in most tertiary care centers; with the exception of select research settings, most clinical laboratories cannot distinguish between seasonal H1N1, seasonal H3N2, and H1N1 S-OIV strains.
The infection control and occupational health concerns engendered by H1N1 S-OIV and the differential antiviral susceptibility patterns of the pandemic and seasonal strains make this a problematic issue. If all 3 strains continue to circulate in the 2009-2010 season, it will be necessary to develop more advanced diagnostics that can discriminate between strains to guide treatment decisions.
Influenza pandemics have occurred, on average, about 3 times a century throughout recorded history. The recent emergence of the H1N1 S-OIV continues this pattern, 41 years after the last pandemic. The hallmarks of pandemic viruses are a high clinical attack rate resulting from lack of immunity; ease of transmission, enabling worldwide spread; and severity of disease.
It is fortunate that to this point, the disease associated with the H1N1 S-OIV has not been as severe as was anticipated during pandemic planning for the highly lethal H5N1 viruses emerging from chickens in Southeast Asia. Nevertheless, this virus, like all influenza viruses, has the capacity to kill, and the sheer number of persons it will infect ensures that the death toll will be nontrivial. Like all influenza viruses, it is a mutable foe that has the capacity to adapt and gain virulence, providing a warning that it should not be taken lightly.
One of the early mysteries is why elderly persons appear to be relatively spared, while healthy children and young adults are disproportionately affected. The answer is likely a combination of immunity resulting from exposure to similar viruses that circulated in the 1930s and 1940s, coupled with an overactive immune response in persons who have experienced infection with poorly related viruses, creating an immunological mismatch.
Children have occupied a central role in this pandemic (Table 3).
They have been the primary vector for transmission in the early stages. Most patients with severe disease have been children and young adults. Although containment efforts using antiviral prophylaxis failed and the pandemic strain rapidly spread worldwide, treatment with antivirals is possible at present, and a vaccine is being prepared.
Equitable and timely distribution of the vaccine in the United States is likely to be a massive and complicated undertaking this fall and winter. Difficulties with distribution and a public debate about prioritization are likely to ensue, but most authorities are in agreement that vaccination of children will be a priority. Regardless of the outcomes or difficulties encountered, the lessons learned from H1N1 S-OIV will strengthen our preparation for the next, inevitable pandemic, whether it appears next year or in another 40 years.
1. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, Dawood FS, Jain S, Finelli L, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans [published correction appears in
N Engl J Med
. 2009; 361:102].
N Engl J Med
2. Nishiura H, Castillo-Chavez C, Safan M, Chowell G. Transmission potential of the new influenza A(H1N1) virus and its age-specificity in Japan.
. 2009;14:pii: 19227.
3. Perez-Padilla R, de la Rosa-Zamboni, Ponce de Leon S, et al; INER Working Group on Influenza. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico.
N Engl J Med
4. Peiris JS, Poon LL, Guan Y. Emergence of a novel swine-origin influenza A virus (S-OIV) H1N1 virus in humans.
J Clin Virol
5. Smith GJ, Bahl J, Vijaykrishna D, et al. Dating the emergence of pandemic influenza viruses.
Proc Natl Acad Sci U S A
6. Webby RJ, Rossow K, Erickson G, et al. Multiple lineages of antigenically and genetically diverse influenza A virus co-circulate in the United States swine population.
7. World Health Organization. Pandemic (H1N1) 2009-update 59. Laboratory-confirmed cases of pandemic (H1N1) 2009 as officially reported to WHO by States Parties to the IHR (2005). July 27, 2009. http://www.who.int/csr/don/2009_ 07_27/en/index.html. Accessed August 28, 2009.
8. World Health Organization. Human infection with pandemic A (H1N1) 2009 influenza virus: clinical observations in hospitalized patients, Americas, July 2009-update.
Wkly Epidemiol Rec
9. Centers for Disease Control and Prevention. Intensive-care patients with severe novel influenza A (H1N1) virus infection-Michigan, June 2009.
10. Cutler J, Schleihauf E, Hatchette TF, et al; Nova Scotia Human Swine Influenza Investigation Team. Investigation of the first cases of human-to-human infection with the new swine-origin influenza A (H1N1) virus in Canada.
11. Centers for Disease Control and Prevention. Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine.
12. Finelli L, Fiore A, Dhara R, et al. Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection.
13. McCullers JA. Insights into the interaction between influenza virus and pneumococcus.
Clin Microbiol Rev
14. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.
J Infect Dis
15. McCullers JA, Facchini S, Chesney PJ, Webster RG. Influenza B virus encephalitis.
Clin Infect Dis
16. 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
17. Centers for Disease Control and Prevention. Neurologic complications associated with novel influenza A (H1N1) virus infection in children-Dallas, Texas, May 2009.
18. Fiore AE, Shay DK, Broder K, et al; Centers for Disease and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008.
19. Reichert TA, Sugaya N, Fedson DS, et al. The Japanese experience with vaccinating schoolchildren against influenza.
N Engl J Med
20. Madhi SA, Klugman KP; Vaccine Trialist Group. A role for Streptococcus pneumoniae in virus-associated pneumonia.
21. World Health Organization. Strategic Advisory Group of Experts on Immunization-report of the extraordinary meeting on the influenza A (H1N1) 2009 pandemic, 7 July 2009.
Wkly Epidemiol Rec
22. Centers for Disease Control and Prevention. CDC advisors make recommendations for use of vaccine against novel H1N1. July 29, 2009. http://www.cdc.gov/media/pressrel/2009/r090729b.htm. Accessed August 28, 2009.
23. Monto AS. The role of antivirals in the control of influenza.
24. Centers for Disease Control and Prevention. Recommended composition of influenza virus vaccines for use in the 2009-2010 influenza season (northern hemisphere winter).
Wkly Epidemiol Rec
25. Centers for Disease Control and Prevention. Update: infections with a swine-origin influenza A (H1N1) virus-United States and other countries, April 28, 2009.
26. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors.
27. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group.
28. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children [published correction appears in
Pediatr Infect Dis J
Pediatr Infect Dis J
29. Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations.
Arch Intern Med
30. World Health Organization. Pandemic (H1N1) 2009 briefing note 1 viruses resistant to oseltamivir (Tamiflu) identified.
Wkly Epidemiol Rec
31. Straumanis JP, Tapia MD, King JC. Influenza B infection associated with encephalitis: treatment with oseltamivir.
Pediatr Infect Dis J
32. Faix DJ, Sherman SS, Waterman SH. Rapid-test sensitivity for novel swine-origin influenza A (H1N1) virus in humans.
N Engl J Med