Top 11 in 2011

As the year comes to a close, I thought I would share the top 11 posts here at Contagions for this past year. I’m excluding round-ups and the educational chain of infection posts. These chain of infection posts account for over a third of all page views on this blog over the year and all time! So without further ado, here are the top 11 regular posts based on page view stats as of December 29, 2011.

1. Pandemic Influenza: 1510-2010
2. Beyond Pelusium
3. Did India and China Escape the Black Death?
4. Vampire Prevention in Eighth Century Ireland
5. Rinderpest, Measles and Medieval Emerging Infectious Diseases
6. The Vampire in the Plague Pit
7. Hunting Pathogens in the Siberian Permafrost
8. Plague in 18th century Egypt
9. DNA of the Black Death at East Smithfield, London
10. Plague DNA from Late Antique Bavaria
11. Epidemiology of the Russian Flu, 1889-1890

Happy New Year!!

Insights into the pathogenesis of the Spanish Flu

One of the enduring mysteries of influenza is why the 1918 H1N1 influenza, better known as the Spanish Flu, was so unusually deadly. The 2009 H1N1 influenza was certainly capable of creating a pandemic but was not nearly as deadly. Granted most of the fatalities in 1918 had bacterial pneumonia that could probably have been cured today. However, the incidence of fatal viral pneumonia appears to have been much higher in 1918. This viral pneumonia was reported to cause “massive acute pulmonary hemorrhage or pulmonary edema”.

New techniques in reverse genetics have allowed two groups, one from the CDC and the other from Japan, to recreate the 1918 virus. This allows either the whole 1918 virus or specific genes or genetic segments to be directly tested on animals.

Contemporary H1N1 influenza viruses infect the upper airways only. The reconstructed 1918 H1N1 virus creates an intense infection in the lungs of non-human primates that culminated in acute respiratory failure and death. Necropsy results have shown extensive pulmonary edema and hemorrhages not found in animals infected with contemporary H1N1 viruses. Microarray analysis showed that the 1918 virus infected animals mounted a strong but atypical innate immune response.

So what is it about the 1918 H1N1 influenza virus that increases its virulence and triggers such a strong but atypical immune response?

Its been known for some time that the hemagglutinin (HA) gene –responsible for host cell selection and membrane fusion — is critical for the high virulence of the avian viruses. The 1918 H1N1 virus lacks the specific motif identified on the avian HA gene that has been attributed to its virulence. When the 1918 HA gene is added to an otherwise contemporary H1N1 virus, it produced a high lung titer causing severe lung damage in mice with infiltration by neutrophils and alveolar macrophages. The results were similar to the whole reconstructed 1918 H1N1 virus. The exact portion of the HA gene that is critical for its virulence is yet to be determined. It is not very surprising that a viral spike responsible for host cell binding and fusion is involved in expanding the target tissue to the lungs.

The role of the 1918 viral RNA polymerase complex in viral repication. (click to enlarge, from Watanabe & Kawaoka, 2011)

The viral RNA polymerase complex has also been implicated in the high  virulence of the 1918 virus. Unlike contemporary influenza viruses, the 1918 virus replicates in the nasal cavity but also along the trachea and within the lungs. As you can see in the figure to the left, the hybrid virus containing the 1918 RNA polymerase complex and NP gene  (PA, PB1, PB2, and NP genes) and the remainder from a contemporary H1N1 virus replicated in the same tissues as the complete 1918 virus. The contemporary H1N1 virus replicated only in the upper respiratory system. Here we have replication of the hybrid virus without the 1918 HA gene replicating in the lungs. Clearly more research is required to reconcile the HA and RNA polymerase complex results.

Other genes have been implicated in increasing the effectiveness of the 1918 virus but the results are more vague.  The availability to reconstruct all or part of the 1918 H1N1 virus along with the 2009 H1N1 pandemic virus and contemporary drifted H1N1 viruses should mean that we will be able to eventually unravel some of the mysteries of influenza but there is still a long road ahead.

References:

Watanabe, T., & Kawaoka, Y. (2011). Pathogenesis of the 1918 Pandemic Influenza Virus PLoS Pathogens, 7 (1) DOI: 10.1371/journal.ppat.1001218

This review paper is freely available here.

Epidemiology of the Russian flu, 1889-1890

In an effort to extend the data set for influenza pandemic planning, Valleron, Cori, Meurisse, Carrat, and Boëlle gathered data from 15 countries in the northern hemisphere that experienced the ‘Russian flu’ pandemic in the winter of 1889-1890.

The pandemic was first recorded in St. Petersburg, Russia. Within a mere four months it had spread throughout the northern hemisphere. The mortality rate peaked in St Petersburg on December 1, 1889 and in the United States during the week of January 12, 1890. The median elapsed amount of time between the first reported case and peak mortality was five weeks.

Red = peak mortality, Green = past peak. (Valleron et al, PNAS May 11, 2010 vol. 107 no. 19 8778-8781 )

Valleron et al hypothesize that the speed of the transmission was due to the ‘connectedness’ of the cities rather than the mode of transport or the sheer number of travelers. European and American cities were better connected by railroads then than they are today by air and rail.

They found a clinical attack rate of 50% with a median basic reproduction number (R0) of 2.1 for the 96 cities studied. The case fatality rate for 1889 was 0.1 – 0.28% based on direct military data and indirect surveys. Direct data on case fatality rate was established from military reports from the French and British armies and indirect estimates come from the seven Swiss cities and the German army. A potential problem of relying so heavily on military data is that military men (in peacetime in 1889) should be among some of the healthier and robust in the population, while the very young, old, infirm and pregnant women usually fare the worst against influenza. With direct data excluding the most vulnerable it seems likely that the case fatality rate is on the low side. We also need an estimate of how often they correctly diagnosed influenza-like disease.

Based on this data, the 1889 pandemic appears to be similar to the mild pandemics of 1957, 1968 and 2009 and the ‘pseudo-pandemics’ of 1947, and 1977-78. The R0 of 2.0 and clinical attack rates of 30-60% is common among all pandemics from 1889 to 2009. Context does matter a great deal for the R0, so we really need to zoom in on the R0 in particular settings like school children, prisons, labor intensive factories, and the military. The 1918 pandemic stands out only in the case fatality rate (and this makes me wonder about the characteristics of secondary pneumonia in 1918).

We do need to keep in mind that this study only examines the first wave of the 1889 pandemic. This pandemic had staying power. Although it spread quickly in it’s first wave it continued to find susceptible victims for another four seasons until 1893.

Valleron, AJ, Cori A, Valtat S, Meurisse S, Carrat F, & Boëlle PY (2010). Transmissibility and geographic spread of the 1889 influenza pandemic. Proceedings of the National Academy of Sciences of the United States of America, 107 (19), 8778-81 PMID: 20421481