While I was otherwise occupied with family matters last week there was news on the flu front that got past me. Declan Butler at Nature News reported on the extensive efforts to get a handle on the prevalence of swine flu infection in various populations by looking for evidence the immune system has reacted to the presence of the virus. All of the studies mentioned are still underway or being peer reviewed so Butler didn't report results, but Fergus Walsh did report some preliminary but leaked results from one of the smaller studies in the UK. Both reports have interesting information, but I'll start with Walsh's first:
The Health Protection Agency (HPA) has done blood tests of hundreds of children and parents connected to early school outbreaks.
With one school in south west England they tested around 500 people. They found that although around one in 10 children fell ill, three to five times as many got infected and developed antibodies.
After analysing this and other data relating to the number of children being seen by GPs, the HPA has now come up with these interesting (but preliminary) estimates:
- Up to one third of children in swine flu hotspots (such as England and the West Midlands) have already been infected with the H1N1 virus.
- Across the UK up to one in five children has had had swine flu.
- About half of those who get infected show no symptoms.
(Fergus Walsh, BBC)
Other (leaked) findings are that "four in 10" people over the age of 50 have a level of anti-H1N1 antibody thought to b protective while that number under the age 50 falls to 1 in 10. There is not enough information in this report to know when the adult samples were taken and from whom and the basis for the child data is also unclear. It's interesting, of course, but to really know what it means requires much more than this leaked information. You take what you can get, of course, and this is what we have.
The trouble is we don't know exactly what we have. The data on adults seems to be consistent with what we see epidemiologically and what CDC found in an early serosurvey. For some reason us older folks have some protection. Where did we get it? The H1N1 serotype came back in 1977 and has been co-circulating with H3N2 a a seasonal flu. The age difference suggests that the immunity comes from H1N1 circulating before it disappeared the first time as a seasonal flu subtype (it was replaced by H2N2 in the "Asian flu" of 1957), but we know the 1977 variant is almost the same as one around in 1950. Were there more than one? We earlier discussed the observation that there were two H1N1 strains circulating in different parts of the world in 1951 (see posts here and here), with a nasty version in the UK, Canada and New England and a milder version in the rest of the US and Europe. Is one or the other the source of the immunity? Or is the 1977 returnee, almost from a lab accident in Russia or China but almost identical to an isolate from a Russian freezer from 1950, something entirely different and providing no protection?
The suggestion as much as half of infected children may be asymptomatic is also consistent with what we believe about seasonal flu. All this confirms that what makes pandemic flu different in this case is its epidemiology (who is getting infected and dying from it), and that seems to be related to the pattern of immune and susceptibles in the population. So while the pattern is important, the fact that this isn't a more virulent flu virus is a stroke of luck:
Professor Maria Zambon from the HPA [UK Health Protection Agency] said:
"We didn't get the pandemic that we planned for and you might say that we've been lobbed a soft ball. There hasn't been high case mortality, the virus is sensitive to drugs, and we've been able to make vaccine and roll it out. I am incredibly grateful that we are not dealing with a pandemic of H5 (bird flu)." (BBC)
We might find out more from the raft of studies discussed by Butler in his (as usual) excellent Nature News article:
Laboratory-confirmed cases of pandemic H1N1 underestimate the true prevalence by several orders of magnitude, as only a tiny fraction of cases can be tested. Instead, public-health agencies such as the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, use proxy measures, including data on the frequency of people reporting influenza-like symptoms to their doctors.
But testing blood samples for antibodies to pandemic H1N1 is the only definitive way to establish how many people have been exposed to the virus and to begin to estimate how this is changing over time. "Arguably, these data are one of the most important quantities," says Marc Lipsitch, an epidemiologist at the Harvard School of Public Health in Boston, Massachusetts, who is working with the CDC on pandemic flu.
Britain, France and Vietnam are among those farthest ahead with such studies for H1N1. In Britain, Andrew Hayward heads FluWatch, which for the pandemic has scaled up its seasonal-flu work to a Â£2.1-million (US$3.5-million) study co-funded by the Medical Research Council and the Wellcome Trust. Instead of its usual 650-850 subjects, the group will investigate 10,000 subjects, including 2,500 in a serology study to look for antibodies against H1N1 in their blood serum.
“Arguably, these data are one of the most important quantities.” (Declan Butler, Nature News)
Butler's piece goes on to describe some ambitious studies that have been underway in the UK, France and Vietnam almost since the outset (and in one case, including sera from just before the pandemic). He reveals no leaked data, which, while always tantalizing, is often too preliminary and lacking in required details, as we saw with the BBC report. Alas, once they are reported it is hard not to comment on them. What Butler's piece provides is context and a much wider view of what is happening and where (UK, France, Vietnam).
An interesting -- and disturbing -- aspect is how the US has lagged behind. It's not because they hadn't planned to do seroprevalence surveys in a pandemic. They had. In concept they are relatively straightforward, but in practice can be difficult. You have to have things ready and the nasty details worked out and resources allocated. Apparently that didn't happen in the US:
Academic groups there are still in the process of applying for funds for such surveys, and Nature has also learned that the CDC is about to announce a serology study across ten states. During pandemic planning before the current virus arose, the United States extensively discussed the need for such studies but decisions weren't taken, says Donald Burke, dean of the Graduate School of Public Health at the University of Pittsburgh in Pennsylvania: "None of these very important studies were in place when we knew there was going to be a pandemic. It's unfortunate." (Nature News)
Yes, "unfortunate" is the right word. If you are prone to understatement.
Note also the slippage from "although around one in 10 children fell ill, three to five times as many got infected and developed antibodies." to "About half of those [including adults perhaps?] who get infected show no symptoms." to your "as much as half of infected children may be asymptomatic". Is the factor <= 2, or is it between 3 and 5? I had the impression, and what you say tends to reinforce it, that you wouldn't expect more than half the cases of seasonal flu to be asymptomatic. If in this case four-fifths (or do they mean five-sixths?) of cases were asymptomatic, that could be an important difference.
oops... by which we multiply the symptomatic cases to get the infected cases up to 2, or is it between 3 and 5 (or do they mean between 4 and 6, it isn't clear whether the "three to five times as many" includes the symptomatic ones or not)? I had the impression that for seasonal flu 2 is a more reasonable estimate; if for pandemic flu the factor is up around 5, that could be a very important difference (that could well explain why we in the UK have not seen the explosion we were expecting, for example).
Revere. Can they tell the difference between virus antibodies and vaccine antibodies?
"Or is the 1977 returnee, almost certainly the source of a lab accident in Russia or China but almost identical to an isolate from a Russian freezer from 1950, something entirely different and providing no protection?"
Revere, is this generally accepted in the influenza community? My understanding was this was still a subject of controversy, but would love to be shown I'm wrong.
Tom: Good question. I suspect the answer is "no."
Sock: The Russians and Chinese deny it. I think most others accept it. Vincent Rancaniello at Virology blog was in Palese's lab when it was discovered and he had a piece on it there (don't have the link handy, alas).
Link to the blog post by Vincent Rancaniello where he writes about the 1977 re-emergence of H1N1:
"The suggestion is clear: the virus was frozen in a laboratory freezer since 1950, and was released, either by intent or accident, in 1977. This possibility has been denied by Chinese and Russian scientists, but remains to this day the only scientifically plausible explanation."
Fascinating. I wish I could do a blood serum study of my family.
Pandemic (H1N1) 2009 in England: an overview of initial
epidemiological findings and implications for the second
JJ: Thanks for the link. This came out at a time when I was out of action but I heard that BBC broke an embargo and the lack of detail suggests they hadn't seen any documents but only had it described.
Just out of curiosity, what is the false negative rate for the test(s) used to detect antibody production to swine flu infection? False positive rate?
ipmat: I don't know but it may well be lab and reagent specific making it hard to compare.
Thanks revere. I wondered how it compared with the 50% false negative rate for quickie office flu tests. I was hoping they were using a more accurate test for antibodies.
Huh! The HPA paper at the link (above) is interesting. I remember a bunch of media comments saying schools shouldn't close, because the kids would just gather together and transmit flu among themselves outside school. I always thought that was stretching it, because outside of huge parties, most kids don't cluster in groups as large as their average class. So their contacts when school closed should decrease, not increase.
Now I read "First, the decline in the number of cases began just before the closure of schools for the summer holidays; cases decreased by approximately 30% to 50% each week after schools closed."
Followed later by "However, with the resumption of school in September, an upward trend in cases began. By 27 September 28, schools with virologically-confirmed pandemic influenza were reported from eight regions" and 25 more had high absenteeism from ILI.
Kinda sounds to me like if we get Pandemic 2.0, high CFR type, we ought to shut the schools pronto.
About the vaccine antibodies part, the UK didn't start vaccinating people till November. I believe the UK samples were taken much earlier than that.
ipmat: The same indications come from the 1957 experience (I will try to post on it if I have time), so I am coming around to the importance of the school closure issue, too. We are still trying to figure all this out. It is a high stakes manouver because of the cost and impact on people's lives.
SusanCC: Yes, you are right. But I think the question was a more general one, especially as seroprevalence surveys get underway and a significant proportion of people will have been vaccinated.
Regarding the effect of schools, given the many week difference in school starting times across the country, the US did do a natural experiment on this. Someone just has to pull together the data.
Here in GA (and neighboring states) schools let out in mid May and restarted in early August (Aug 10th was typical). In many northern states, the time frame is shifted about a month: schools ended mid June, restarted early Sept.
I know the data in GA is that the current swine flu case numbers took off by late Aug, peaked in Sept, and we are currently below 20% of the Sept peak. And if you look at the age group breakdown, the 5-18 yo group led the others (going up, and going down).
This page of the GA Dept of Comm Health shows the age breakdown for the state for the last week, and just below that table is a link to prior weeks data going back to the begining of Sept.
If other states have similar data, the effect should be pretty easy to spot. At least the regional data at the CDC website shows, for example, that the New England region was about a month behind GA.
One of the positives aspects of this H1N1 outbreak may be that it's timing, where schools let out before it had a chance to run its natural course, has given us an opportunity to get a measure of the importance of schools in the spead of the disease.
Revere, you wrote
almost certainly the source of a lab accident in Russia or China...
But I think you meant
almost certainly from a lab accident in Russia or China...
Monado: Yes, I did. Thanks for pointing it out. Will correct.