Severe cases of pandemic influenza

flu-pediatric-deathsThe World Health Organization recently convened a meeting of 100 clinicians, scientists, and public health professionals to discuss the clinical features of pandemic influenza. They concluded that the vast majority of infections with the 2009 H1N1 influenza virus were uncomplicated and are followed by full recovery within 7 days. However, some patients, including children, develop severe, progressive fatal pneumonia. Should we be worried about this pattern of infection?

According to WHO:

Concern is now focused on the clinical course and management of small subsets of patients who rapidly develop very severe progressive pneumonia. Treatment of these patients is difficult and demanding, strongly suggesting that emergency rooms and intensive care units will experience the heaviest burden of patient care during the pandemic. Primary viral pneumonia is the most common finding in severe cases and a frequent cause of death. Secondary bacterial infections have been found in approximately 30% of fatal cases. Respiratory failure and refractory shock have been the most common causes of death.

The risk of severe illness is highest among pregnant women, children less than 2 years of age, and individuals with chronic lung disease. In the US, 86 children under 18 years of age have died from H1N1 influenza infection. This number is unusually high at this early point in the influenza season, and will likely rise as the number of infections increase. Anne Schuchat of CDC has said that “this is a very brisk number, usually in a whole season that lasts from…September all the way to May, you would only have about 40 or 50 deaths so in just one month’s time we’ve had that many.”

Why do some patients develop progressive pneumonia, and why are there so many fatalities in children? There isn’t enough information to answer these questions, but here is my virological perspective. One factor is the unusual genetic makeup of the virus. The results of a number of studies in ferrets, mice, and primates have shown that the 2009 H1N1 influenza virus replicates better than seasonal strains in respiratory tissues, including the lung. One way to understand the basis for this difference is to produce reassortants of the 2009 H1N1 and seasonal H1N1 strains with one or more genomic RNAs exchanged. Does the swine-derived HA of the pandemic H1N1 strain play a role in virulence? Then put the RNA segment for this HA into a seasonal H1N1 virus and determine the effect in ferrets. Such experiments are not always definitive but always worth doing. I’m still not sure that the animal results are predictive of what happens in humans. After all, in all the ferrets and mice inoculated, the pandemic H1N1 strain causes more severe disease. That simply is not the case in humans; severe disease is only seen in rare cases.

Another factor is population immunity. The HA of the 2009 H1N1 virus is swine-derived; we have never had such extensive spread of a swine HA-bearing influenza virus in humans (the 1976 H1N1 swine virus never got out of Fort Dix). The H1N1 virus probably entered humans and pigs around 1918, then evolved independently in both species. The H1N1 virus has circulated in pigs from 1918 to the present. Transmission of the H1N1 virus in humans stopped in 1957 when the virus was replaced by the H2N2 strain. But the 1957 human H1N1 strain, which was reintroduced into people in 1977, is only distantly related to the 2009 swine-origin H1N1. If you were born before 1950, you have some protection against infection with the 2009 H1N1 strain. This factor may contribute to the susceptibility of the pediatric population to severe infection.

The increased risk of pregnant women for developing severe influenza is well known but poorly understood. Pregnant women are in general more susceptible to infectious disease than non-pregnant woman. Hepatitis A, B, and E are more lethal, and paralytic poliomyelitis was more common, in pregnant women than in others. One explanation is that hormonal differences affect immune responses, but the specific mechanism is obscure.

The 2009 influenza H1N1 strain clearly behaves differently than seasonal strains in certain populations. The papers explaining why have yet to be published, but when they do emerge I’ll be explaining them here.

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