Severe cases of pandemic influenza

21 October 2009

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.

Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, Muramoto Y, Tamura D, Sakai-Tagawa Y, Noda T, Sakabe S, Imai M, Hatta Y, Watanabe S, Li C, Yamada S, Fujii K, Murakami S, Imai H, Kakugawa S, Ito M, Takano R, Iwatsuki-Horimoto K, Shimojima M, Horimoto T, Goto H, Takahashi K, Makino A, Ishigaki H, Nakayama M, Okamatsu M, Takahashi K, Warshauer D, Shult PA, Saito R, Suzuki H, Furuta Y, Yamashita M, Mitamura K, Nakano K, Nakamura M, Brockman-Schneider R, Mitamura H, Yamazaki M, Sugaya N, Suresh M, Ozawa M, Neumann G, Gern J, Kida H, Ogasawara K, & Kawaoka Y (2009). In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature, 460 (7258), 1021-5 PMID: 19672242

Maines TR, Jayaraman A, Belser JA, Wadford DA, Pappas C, Zeng H, Gustin KM, Pearce MB, Viswanathan K, Shriver ZH, Raman R, Cox NJ, Sasisekharan R, Katz JM, & Tumpey TM (2009). Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice. Science (New York, N.Y.), 325 (5939), 484-7 PMID: 19574347

Munster VJ, de Wit E, van den Brand JM, Herfst S, Schrauwen EJ, Bestebroer TM, van de Vijver D, Boucher CA, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, & Fouchier RA (2009). Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science (New York, N.Y.), 325 (5939), 481-3 PMID: 19574348

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  • Chad

    Hi Vincent, I was hoping you or anyone else could comment or make a new post with your thoughts on this article (link below) questioning the efficacy of the influenza vaccine. Based on the studies mentioned, it seems that overall the influenza vaccine has had no effect on mortality rates in groups most susceptible to flu. Thanks for your time!

    http://www.theatlantic.com/doc/200911/brownlee-

  • http://www.virology.ws profvrr

    It's an issue of great controversy as you might imagine. There have
    been a good number of epidemiological studies done on this issue and
    most have found little or no benefit from immunizing the elderly. This
    is not true for younger ages, though. The problem is that many of
    these studies were not done properly, so a good one is needed.
    Nevertheless, I don't think anyone would suggest that this age group
    should not be immunized. The problem seems to be a poor immune
    response in those over 65 years of age – so what we need is to develop
    new approaches to stimulate immune responses in this age group. By the
    way, most of the influenza mortality in non-pandemic years is due to
    infections of the over-65 year old population; that's why they are
    targeted for immunization.

  • http://www.virology.ws profvrr

    It's an issue of great controversy as you might imagine. There have
    been a good number of epidemiological studies done on this issue and
    most have found little or no benefit from immunizing the elderly. This
    is not true for younger ages, though. The problem is that many of
    these studies were not done properly, so a good one is needed.
    Nevertheless, I don't think anyone would suggest that this age group
    should not be immunized. The problem seems to be a poor immune
    response in those over 65 years of age – so what we need is to develop
    new approaches to stimulate immune responses in this age group. By the
    way, most of the influenza mortality in non-pandemic years is due to
    infections of the over-65 year old population; that's why they are
    targeted for immunization.

  • himanshu_sharma

    “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.”
    From this I can understand that H1N1 was replaced by a less virulent H2N2 in 1957,but your very next statement that H1N1 was reintroduced into people in 1977,i didn't understand that.It should be H2N2(as it is has replaced H1N1) getting reintroduced into people in 1977.Also can you please elaborate more on how people born before1950 have a specific immunity towards 2009 swine flu virus?

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  • http://www.virology.ws profvrr

    The H1N1 virus that disappeared in 1957 re-emerged in 1977. You might want to read the post “Origin of contemporary H1N1 influenza virus” at http://www.virology.ws/2009/03/02/origin-of-cur… for clarification. Influenza viruses that circulated in the 1940s are antigenically similar to the 2009 H1N1 virus and hence infection confers some protection.

  • Marcello Pucciarelli

    I wonder whether a mathematical model such as the one proposed by Mohtashemi and Levins (Transient dynamics and early diagnostics in infectious disease, J.Math.Biol. 2001) has found application in the study of severe illness caused by influenza. The model emphasizes the importance of the duration of the period of inactivity of the immune system after invasion: with increased duration of immune inactivity the pathogenic load increases exponentially, the peak of infection is reached earlier and the peak has a greater intensity.

    It is a difficult paper (for me), and its equations are far beyond my understanding. It seems, however, that by feeding the model with appropriate parameters (e.g., reproductive rates, rates of induction of the immune system) it could be possible to get some insights about severe illness, even in cases where the specificity of action of the pathogen is poorly understood.

  • marcellopucciarelli

    I wonder whether a mathematical model such as the one proposed by Mohtashemi and Levins (Transient dynamics and early diagnostics in infectious disease, J.Math.Biol. 2001) has found application in the study of severe illness caused by influenza. The model emphasizes the importance of the duration of the period of inactivity of the immune system after invasion: with increased duration of immune inactivity the pathogenic load increases exponentially, the peak of infection is reached earlier and the peak has a greater intensity.

    It is a difficult paper (for me), and its equations are far beyond my understanding. It seems, however, that by feeding the model with appropriate parameters (e.g., reproductive rates, rates of induction of the immune system) it could be possible to get some insights about severe illness, even in cases where the specificity of action of the pathogen is poorly understood.

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    H1N1 didn't live up to all those pandemic expectations.

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