Swine-origin influenza virus A(H1N1)v: lessons learnt from the early phase of the epidemic Free

In late March 2009, Mexican authorities identified an unexpected increase in the number of cases of influenza-like illness (ILI), including a higher than expected number of cases of severe pneumonia characterized by respiratory distress syndrome.¹ At the beginning of April, a novel influenza virus A/(H1N1) variant (H1N1v) of apparent swine origin was identified by the US Centers for Disease Control and Prevention in two children in California.² The same variant was then identified in Canada in biological samples from a Mexican patient with ILI. The evidence of sustained community transmission of H1N1v in different countries on more than one continent led the World Health Organization (WHO) to declare Phase 6 of pandemic alert (‘The Pandemic Phase’).

H1N1v appears to have derived from a further reassortment of a triple reassortant North American swine virus with the NA and M segments of a European swine virus.³ However, when and where this variant emerged remain unknown, though phylogenetic analyses suggest that it had been circulating for a number of years before trans-species passage and adaptation to the human host.⁴

H1N1v is efficiently transmitted among humans, probably through the same modalities as seasonal influenza viruses, that is, through large droplets or contact with contaminated surfaces. Moreover, because the variant is novel, much of the population is susceptible, increasing the potential for spread.

Since the time of the identification of H1N1v, several lessons have been learned, though there are also some gaps in the current knowledge that need to be bridged.

The estimated basic reproductive rate (R₀) for H1N1v is around 1.5,⁵ though this may not reflect the high attack rates experienced by school populations. According to mathematical models that simulate the emergence of human cases of infection with the avian virus H5N1, containment would be possible in cases in which the R₀'s were between 1.8 and 2.4,^6,7 through such measures as social distancing, anti-viral prophylaxis, pre-vaccination and quarantine. Although the R₀ for H1N1v might be even lower than this range, it remains to be determined why the early isolation of cases and the quarantine of close contacts were able to contain outbreaks of SARS, whose estimated R₀ was 2–4, but not outbreaks of H1N1v. One explanation is that the early chains of inter-human transmission were not identified. An important role could also be played by other factors, such as the serial interval between two consecutive cases, which is lower for influenza than for SARS, and the peak of viral shedding, which is much shorter for influenza (1 day versus 1 week for SARS). Moreover, the milder the symptoms, the lower the probability of identifying infectious individuals (i.e. mild and asymptomatic cases being unidentified sources of H1N1v infection transmission). This may explain why distancing may only delay and/or mitigate (but not definitely contain) influenza outbreaks.

That a high proportion of cases was identified among travellers and their close contacts before the occurrence of school outbreaks, and the sustained community spread in a previously unaffected country highlights the important role played by international travel in the global spread of influenza. However, the contradictions present in this globalized world must be considered: we can monitor in real time the spread of the infection through international travel, yet we have not been able to effectively intervene. In this regard, the position of WHO is paradigmatic, in that travel restriction is considered as inefficient in terms of cost-effectiveness.

As with previous pandemics, the age distribution of infection with this variant differs from that of seasonal influenza, with most cases having occurred among individuals aged <60 years. This pattern appears to be typical of pandemic viruses. However, it remains to be defined whether this is related to immune protection consequent to previous exposure to similar viruses or whether older people have not been hit yet because of the specific dynamics of the epidemic, with travellers and school populations being affected earlier and older persons later, as suggested by the recent increases in the age of infected individuals. In this regard, a study conducted in the USA showed that about one-third of individuals aged >60 years had protective antibodies against H1N1v.⁸

The clinical spectrum of infection with H1N1v remains to be defined. Severe cases of pneumonia and respiratory distress syndrome have been reported in previously healthy young adults in Mexico.⁹ However, most cases appear to be mild. In Europe and the USA, most severe cases (though not all of them) occurred in individuals with chronic disorders, who are also at higher risk of complications of seasonal influenza. Pregnant women and obese individuals also appear to be at higher risk of developing severe disease. Geographical differences in case-fatality rates may be related to unidentified host-related or environmental factors, small changes in the viral genome and differences in healthcare systems, in access to care, and in the underreporting of cases with mild to moderate disease.

Indications for anti-viral drug use for chemoprophylaxis of close contacts and treatment of cases may vary during the course of a pandemic. In the containment/delay phase of the current pandemic, anti-viral drugs (i.e. the neuraminidase inhibitors oseltamivir and zanamivir) were provided to all cases and to their close contacts, in order to reduce the risk of transmission. Once the epidemic progresses and becomes widespread at the community level, anti-viral drugs should be spared and limited to the treatment of persons at high risk. The occurrence of sporadic cases of resistance to anti-viral drugs after chemoprophylaxis or treatment¹⁰ is alarming. Whether these cases are early predictors of widespread resistance in further epidemic phases remains unknown.

The extent to which mass vaccination may be considered as a valid option is a matter of debate. Decision making in public health continues to be influenced by the USA's experience with Guillain–Barré Syndrome, of which there were numerous cases after the vaccination of millions of people in 1976. Who should be vaccinated is also a challenging question. People at risk of severe disease should be a priority. Essential workers, including health care workers, should also be protected. Whether school children and adolescents should be a target, due to their role as epidemic amplifiers, is debated.

Finally, though past experience may help to understand new phenomena such as an emerging pandemic, history does not necessarily repeat itself. The Spanish flu epidemic was characterized by at least two sequential waves: the first wave, which was mild, occurred at the end of the influenza season in March 1918, whereas the second one, which was more aggressive, began in August; changes in clinical severity were likely due to unrecognized viral mutations. With the novel H1N1 variant, we are observing a mounting tide, with an increasing number of cases worldwide. While a further increase in the incidence of new cases in autumn is expected in the northern hemisphere, the occurrence of viral mutation remains unpredictable.

In conclusion, many lessons have been learned from this early pandemic phase, though several caveats in our knowledge still remain. Although our capacity to follow in real-time virus movements and changes has improved, preparedness efforts have not been able to contain initial outbreaks. Whether mitigation and treatment will be successful in reducing the global impact of the pandemic is under evaluation.

Conflicts of interest: None declared.

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