Swine Flu — Where Did It Come From, Where Is It Going?
Abstract & Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
The emergence of a new H1N1 influenza virus has triggered worldwide preparations for a pandemic. On April 29, 2009, the World Health Organization (WHO) announced that the problem deserved a phase 5 designation, which indicates sustained human-to-human transmission of a novel influenza strain of animal origin in two countries within one region, but with exportation to countries outside that region (see Figure 1). The first identified case, thus far, in the current pandemic occurred on March 18, 2009, in Mexico. Molecular analysis, however, suggests that the first cases may have occurred in mid-September 2008 when the most recent common ancestral virus is calculated to have emerged. Initial evidence suggested that the virus originated in swine, resulting in its being referred to as swine flu.
Swine have generally been considered a frequent "mixing vessel" in which new strains of influenza virus emerge as the result of reassortment between avian and human or swine viruses (although there has been no evidence developed that the 1957 and 1968 pandemics caused by reassortments of human and avian viruses came from pigs). The resultant virus may infect humans, but usually only as the result of direct contact and with no secondary human cases. The occurrence in 1976, however, of several hundred cases of human infection and the death of Pvt. David Lewis at Fort Dix, New Jersey, led to the development and administration of a vaccine (A/NewJersey/1976/H1N1) to approximately 40 million people in the United States. Unfortunately, there were also approximately 500 cases of Guillain-Barré associated with its administration, and the program was aborted. That epidemic did not spread beyond Fort Dix.
Evidence indicates that the current virus is a descendant of an ancestral triple reassortant swine virus, with elements from swine, avian, and human viruses that likely had been circulating in swine for perhaps 20 years, with limited ability to infect humans. A 17-year-old boy in Wisconsin who had butchered pigs was infected with this virus in December 2005,1 with no identified secondary cases. Since then, an additional 10 cases have been identified.2 Nine of the 11 patients had contact with pigs; all 11 survived. The triple assortant subsequently gained the ability to efficiently infect and, more importantly, spread among humans as the result of further recombination with a Eurasian swine virus, resulting in swine-origin influenza A (H1N1) virus (S-OIV).3,4 The resultant virus also has been called A/California/04/2009, since the first isolate identified was recovered from a child in San Diego. Of note, is that there is no evidence, as yet, that S-OIV is epidemic in pigs — this is now a human, not a swine disease. In fact, the first known report of this virus in a pig population resulted from transmission from a worker who returned from vacation in Mexico to Alberta, Canada, and caused an outbreak resulting in symptomatic illness in approximately one-fourth of 2000 pigs.5 Thus, the only evidence of zoonotic transmission to date is from human to swine, not the other way around.
Clinical symptoms of S-OIV infection are typical of influenza, except for a higher incidence of vomiting and diarrhea, each of which have occurred in approximately one-fourth of cases. The age distribution of cases is similar to that of seasonal influenza, with 60% occurring before 19 years of age. The U.S. deaths have occurred in patients with significant underlying illnesses. In California, 553 confirmed or probable cases had been identified by May 17, 2009 and 30 of these required hospitalization.6 In contrast to other reports indicating lower sensitivity, rapid antigen tests for influenza A were positive 67% of the 24 hospitalized patients tested and in contrast to the Mexican experience, diarrhea was uncommon. Apparent pneumonia was present on chest Xray in 15 or 25 patients (60%) in whom this was performed; 10 of these had multilobar infiltrates. Six patients required mechanical ventilation. None of the 30 patients had microbiologic evidence of secondary bacterial infection. Nineteen patients (64%) had underlying medical conditions, including five who were pregnant. Two of these five suffered complications, including spontaneous abortion and premature rupture of membranes. The virus, in contrast to the recently circulating seasonal H1N1 influenza, is susceptible to oseltamivir, as well as to zanamivir, but resistant to the adamantines.
Modeling of the epidemic to date suggests (albeit with substantial uncertainty) that the initial report of fatalities in Mexico was not the result of significantly enhanced virulence, but simply a reflection of the large number of cases that already had occurred by that time.4 The investigators estimate that there had, in fact, been 23,000 cases (range 6,000-32,000) by late April, with an estimated case fatality rate of 0.4% (range 0.3% to 1.5%), a rate substantially less than that associated with the 1918 pandemic, but approximately the same as that in 1957-1958 (the Asian flu) pandemic. The estimated transmissibility of the current virus is also not far from the norm. Depending on the methodology used, the calculated basic reproduction number (R0; the number of secondary infections produced by a single infected individual) is 1.2-1.6. This number is similar to that seen with seasonal influenza, while comparable estimates of R0 for the 1918, 1957, and 1968 pandemics ranged from 1.4-2.0. The WHO, however, suggests that there may be a much higher secondary attack rate.
Commentary
The recognition that the initial perception of a high mortality rate was apparently spurious has led to some relaxation of concern. This may, however, be premature. While we have completed the usual influenza season in the Northern Hemisphere, the season is just beginning in the southern latitudes. Furthermore, previous pandemics have come in waves, with the second or third wave sometimes being associated with more severe disease than the original portion of the epidemic. While this was not true of the 1968 pandemic, it was true in 1957-1959 and, especially, in 1918. In fact, concern has been raised about the possible recombination of S-OIV with avian influenza, with the potential for significantly enhance virulence in a virus with a high degree of human-to-human transmissibility.
References:
- Newman AP, et al. Human case of swine influenza A (H1N1) triple reassortant virus infection, Wisconsin. Emerg Infect Dis. 2008;14:14702.
- Shinde V, et al. Triple-reassortment swine influenza A (H1) in humans in the United States, 2005-9. N Engl J Med. 2009;361: May 7. [Epub ahead of print]
- Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009; 361: May 7. [Epub ahead of print]
- Belshe RB. Implications of the emergence of a novel H1 influenza virus. N Engl J Med. 2009;361: May 7. [Epub ahead of print]
- Fraser C, et al. Pandemic potential of a strain of influenza A (H1N1): Early findings. Science. 2009 11 May 2009 [Epub ahead of print]
- Influenza A (H1N1): animal health (09), swine, Canada. http://www.promedmail.org
- CDC. Hospitalized patients with novel influenza A (H1N1) virus infection --- California, April – May, 20009. May 18, 2008 / 58(Early Release);1-5.
Internet Resources:
- Centers for Disease Control; http://www.cdc.gov/h1n1flu/index.htm U.S. Government Pandemic Influenza Site: http://www.PandemicFlu.gov/
- U.S. Government Pandemic Influenza Site: http://www.PandemicFlu.gov/
- World Health Organization http://www.who.int/csr/disease/swineflu/en/index.html
- Human/Swine A/H1N1 Influenza Origins and Evolution (Wiki) http://tree.bio.ed.ac.uk/groups/influenza/
- http://www.thelancet.com/H1N1-flu
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