Effect Measure

Flu rolls into town

When my colleagues announced early afternoon on Friday he was headed home because he was sick, I knew the flu had finally arrived on my doorstep. It was already here, of course. The emergency rooms are jammed, clinics have long waits and hospital admissions for flu are up — way up. The flu situation was the page one column eight story in Saturday’s Boston Globe:

The flu virus is rampaging across New England, spawning waves of coughs and fevers, causing patients to flood doctors’ offices, and raising questions about the effectiveness of flu shots given to tens of millions of Americans.

During the past two winters, the influenza season proved unusually mild in New England and much of the nation. But this year is strikingly different, with federal disease specialists reporting yesterday that virtually every state now has widespread flu activity.

“We’re seeing it raging,” said Dr. Alfred DeMaria, the top disease tracker in Massachusetts.

At Massachusetts General Hospital’s network of clinics and hospital wards, the number of patients testing positive for influenza so far this season is already 21 percent higher than for all of last winter.

At Harvard Vanguard Medical Associates, doctors report that their patients must sometimes wait an hour for care because so many people are showing up with flu symptoms.

And at Boston’s Health Department, the tally of laboratory-confirmed flu cases last week reached its highest level since the city started intensively tracking lab results four or five years ago. (Stephen Smith, Boston.com)

But you probably know this already, at least those of you in the northern hemisphere. Our many readers in Oz (Australia, New Zealand) have been through it already (see here and here). Now it’s our turn.

The season started with most subtyped influenza A viruses being H1N1. But like last year, the balance is shifting from the H1N1 subtype to the H3N2 subtype, although there is regional variation in the relative proportions of H1 and H3. H1 years tend to be milder than H3 years, so keeping track is of some interest. This year’s flu vaccine is well matched for H1N1 but not for H3N2 (see here, here), so this is not a good development. More important than the relative proportions is the sudden increase in incidence (number of new cases in a time period). 44 US states are now reporting widespread flu activity. The flu is also killing people, as it does every year:

Pneumonia and influenza (P&I) was listed as an underlying or contributing cause of death for 7.6% of all deaths reported through the 122 Cities Mortality Reporting System for the week ending February 9. This percentage was above the epidemic threshold of 7.2% for the week and marked the fifth consecutive week that P&I deaths were above the epidemic threshold since influenza activity began rising in the United States (figure 4). (CDC Update: Influenza Activity)

i-74c07ce30d33cb737b8c186690e04a81-m7e215a1f4.gif

As the figure shows, the last two years were relatively mild. 2003 was another bad year. We still don’t know how this one will shape up, but the strain mismatch in two of the three components of this year’s flu vaccine won’t help (influenza B, the third component of the vaccine was also mismatched; flu/B accounts for about 16% of the ascertained flu diagnoses so far). On at least three measures this season is worse than any of the previous three (2004, 2005, 2006; this is the 2007 season): this year there is widespread or regional activity in 49 states compared to a high of 48 for the previous three years; this year 33% of specimens tested are positive compared to a high of 28% for the previous three years; and this year, most recently 5.7% of visits to a set of surveillance practices are for influenza-like illness, while the highest level for any week of the previous three years was 5.4%. So in comparison, this is already the worst year since 2003 and may get worse still.

A new wrinkle this year is the appearance of a mutation (H274Y) in a small proportion of H1N1 isolates thought to confer resistance to Tamiflu. So far H3N2 and flu/B are not affected. All subtypes remain sensitive to the other neuraminidase inhibitor, Relenza (zanamivir), but this drug must be inhaled and doesn’t work for systemic infections. It is also not recommended for children. Tamiflu is still recommended for prophylaxis or early treatment of influenza.

Bird flu is also flu and there is a noticeable increase in the number of reported H5N1 cases as well (see here for depiction of confirmed cases through February 5).

So far, the best summary is this: it’s flu season.

Comments

  1. #1 Jeb, FCD
    February 17, 2008

    My wife and I just got over this flu. Luckily, as I was getting sick we got Tamiflu for myself and our four year old. It skipped him entirely. My course was shortened, though I did develop laryngitis for a week.

  2. #2 Coturnix
    February 17, 2008

    We were all in bed this week, all four of us…

  3. #3 Racter
    February 17, 2008

    >>This year’s flu vaccine is well matched for H1N1 but not for H3N2

    According to the CDC — which, on Friday’s update, has 91% of the isolates in the U.S. as a good antigenic match with the A/Solomon Islands/3/2006 component of this year’s vaccine. But on Thursday, the WHO announced that even though (globally) the majority of influenza A(H1N1) viruses was closely related to A/Solomon Islands/3/2006, they were recommending A/Brisbane/59/2007 for next year.

    I can’t help wondering if those sessions ever erupt in fisticuffs.

  4. #4 miso
    February 17, 2008

    “…Relenza (zanamivir), but this drug must be inhaled and doesn’t work for systemic infections.”

    Let’s not forget that flu starts in the lungs, if you’ve waited long enough for it to spread neither Tamiflu nor Relenza is going to save you much bed time. Isn’t that the escape clause for Tamiflu treated bird flu victims that die?

  5. #5 miso
    February 17, 2008

    P.S. injected zanamivir does work for systemic infections, only GSK pulled the plug on successful clinical trials in the late nineties because Tamiflu replaced Relenza in the seasonal flu market,.. hardly a life or death decision at the time, but even now GSK refuse to fund further trials. There’s more money in vaccines.

  6. #6 Monado, FCD
    February 17, 2008

    How do health authorities know the incidence of flu? Most people with tht flu don’t drag themselves to a doctor – they just hole up for a week or so. And we’re discouraged from going to the Emergency Department, because it’s a viral disease (so antibiotics won’t work on it) and we can spread it to others.

  7. #7 Exoteric
    February 17, 2008

    Given your somewhat frequent references to The Boston Globe, it seems likely you live in Boston. In that case, you seem to be well placed to talk to your colleague in the study of public health matters, Professor Edward Giovannucci of the Departments of Nutrition and Epidemiology, at the Harvard School of Public Health. If you ask him if he’s aware of any new, candidate explanation for the cyclical, annual nature of influenza’s variable intensity, I think you’ll find his reply very interesting and suggestive. He may also introduce you to an acquaintance at the Boston University School of Medicine, who will be able to set the matter in its wider context.

  8. #8 miso
    February 17, 2008

    P.P.S. Here’s something no-one ever criticizes Tamiflu for. It’s all well and good that it is take orally, but IT CAN”T BE INJECTED.

    “zanamivir is not used because it is an inhaler and patients in the recent Asian outbreak were too ill to inhale even though laboratory tests show it has some effects on H5N1. Manufacturers should think about producing an injectable form. Drugs that are administered intravenously can be better absorbed in patients who have stomach and acidity problems. We don’t have to worry about absorption, injections take drugs right in. But if the patient takes them orally, maybe some amounts won’t be absorbed or some may be destroyed by stomach acids. Intravenous zanamivir would also ensure faster onset, which would be critical in patients who are seriously ill. Orally taken drugs take 3-4 hours to reach maximum blood concentration and 3-4 hours is very critical in severe cases. But injectable zanamivir takes only 30 minutes to reach maximum blood concentration, this is a huge difference. With an intravenous antiviral, doctors can also vary the doses.”

    Source: http://focosi.altervista.org/pathoviruses_influenzaA.html

    Perhaps instead of criticize Relenza because it is inhaled, people should be writing to GSK, and asking them what the f*ck they are thinking.

  9. #9 revere
    February 17, 2008

    Monado: You ask a good question. It has to be estimated. There is a rather extensive and overlapping series of surveillance systems. If you go to the CDC Flu Update link in the post you can read about it. Estimating excess mortality from flu is a difficult task and a small industry in itself.

    Exoteric: The Boston Globe, like other newspapers, has a website Boston.com. They show up on news aggregators. If you check posts here you will in fact see the Globe show up very infrequently. I can think of less than a dozen, maybe a half dozen times in a few thousand posts. There are lots of LA Times, Atlanta Journal Cosntitution, NYT, of course Canadian newspapers. Maybe the Reveres are Canadian? We don’t give clues but one thing you shouldn’t use as an indication of anything is how often we cite a news source.

    miso: You are always a staunch advocate of zanamivir here, which is fine. I think it should be used more, too. But it isn’t so we don’t talk about it as much. It has its plusses and its minuses. I don’t mind your advocacy and it keeps reminding me to mention it more.

  10. #10 Exoteric
    February 17, 2008

    The flu situation was the page one column eight story in Saturday’s Boston Globe….

    My news aggregators don’t refer to articles by page and column numbers, and I’m inclined to suppose that someone who makes such a reference has the newspaper on his desk. Moreover, if I were to write about “the flu situation,” as the flu “rolls into town,” I would cite a news source from the 30th parallel, so I think I understand well enough why you chose the 42nd parallel. Now, lives are at stake, so Revere, why don’t you just get on your horse, gallop across Boston again, and have a little chat with Prof. Giovannucci and his colleague, like the nice commenter suggested? Oh, that’s right; Bush has the Mossad out looking for you, and you’re scared. Never mind. :-)

  11. #11 revere
    February 17, 2008

    Exoteric: I’ll break a rule. This revere doesn’t live in Boston (nor does Revere). And regarding your point about the paper copy, this is a good observation. We don’t claim we never visit Boston. Especially when it hosts one of the largest scientific meetings in the world (AAAS).

  12. #12 miso
    February 17, 2008

    revere,
    It’s not like Tamiflu needed any more staunch advocates, I’m just trying to redress the imbalance by taunting the “conventional wisdom”ists.

    I’m also just assuming injectable Tamiflu is impractical; but then if Relenza is any indication, accountants are making all the decisions at Roche and GSK,…heaven help us.

  13. #13 highflyer
    February 18, 2008

    miso: “if you’ve waited long enough for it to spread neither Tamiflu nor Relenza is going to save you much bed time. Isn’t that the escape clause for Tamiflu treated bird flu victims that die?”

    Not really. There is general agreement about the sooner the better. But there is no “escape clause” for H5N1 victims, there is just anecdotal evidence that it might still be worth while to treat them even late in the course of illness.
    http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/dec1206antiviral.html
    The same applies to seasonal influenza. Again, if there is a patient with serious illness or a high risk profile (cardiovascular disease, just to name one), they might still profit from late treatment, not so much for “bed time” but for lowering the rate of complications.

    I do not know for sure wether there are currently any Relenza trials for an injectable preparation going on and if not, why not. The last news about that I read was that they could not find a future customer to buy the injectable form and thus put it on hold.
    I doubt a major benefit for injectable versus tablet in the case of influenza. The major benefit for Zanamivir would have been (or still could be?)to make it systemically available. And not all studies regarding that have ceased, at least animal studies are still going on:
    http://www.influenza-info.org/pdfs/posters/p0122.pdf

    miso: “accountants are making all the decisions at Roche and GSK,…heaven help us.”
    I would rather blame politicians for that than the companies, in both instances. If they do not order enough or at least promise big orders, production capacity is reduced or not even attempted. That same problem applies to
    vaccine development and production as well.

    Which brings us back to the priority issues of spending. At least in Europe there was a fast reaction to the increased resistance observed, in terms of a recommendation at least. Which might be lip service and not more, but a start.

    At least Peramivir still seems to be in the race
    http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/sep2007peramivir.html

    A reaction in Europe to the resistance issue and Relenza (excerpt from the source below):
    http://www.webwire.com/ViewPressRel.asp?aId=57800

    GlaxoSmithKline welcomes European guidance that stockpiling more than one antiviral would be useful in preparing for a flu pandemicWEBWIRE – Tuesday, January 29, 2008
    Not for distribution to US Media

    Both zanamivir ( Relenza ) and oseltamivir (Tamiflu) are recommended as candidates

    GlaxoSmithKline (GSK) welcomes the new guidance from the European Medicines Agency (EMEA) on the use of antivirals during a flu pandemic and the recommendation that the availability of more than one antiviral would be useful in preparing for a flu pandemic.[1] The guidance has been revised in light of new evidence including emerging viral resistance. ……….

  14. #14 wenchacha
    February 18, 2008

    To revisit an issue that has been discussed several times on several H5N1 web fora: instead of the intravenous mode, can Tamiflu or Relenza work as a suppository? You bypass the stomach acid, and you get to the bloodstream quickly. It also eliminates (!) the risk of vomiting back the medicine.

  15. #15 revere
    February 18, 2008

    wenchacha: The tablet form, oseltamivir phosphate (Tamiflu), has no activity against the virus. It is what is called a pro-drug. Once absorbed it is converted by an enzyme in the liver (a carboxylesterase) to its active carboxylate form. The inactive form in the tablet can be absorbed but the active carboxylate cannot. Relenza is already in the active form and cannot be absorbed, which is why it is given by inhalation and only works in the lung (so infections in other tissues are not affected).

    The implications here are that Tamiflu would work as a suppository (because it can be absorbed there and these blood vessels go through the liver first, just as in intestinal absorption) but Relenza cannot (because it cannot be absorbed). However Relenza can be given intravenously since it doesn’t need activation and this doesn’t require absorption. This makes it suitable for therapeutic purposes in the hospital but not for prophylaxis. As commenter miso points out, the maker of Relenza, GlaxoSmithKline, has failed to develop an intravenous form so none now exists.

  16. #16 bar
    February 18, 2008

    It’s way out of my expertise, but:

    When we first got penicillin, back in the ’30s or ’40s, it worked on nearly everything. Now we have golden staph et al.

    Could something similar be happening to our annual flu shots?

    e.g. By inoculating above a threshold proportion of the population the chosen strain is attenuated, so mildly infected persons do not stay at home, thus more people are infected, thus an enlarged reservoir from which potentially hazardous mutations might evolve.

  17. #17 no thanks
    February 20, 2008

    Is it the flu, or something else going around, that produces a 2-week headache (mostly frontal), minor stuffy/runny nose, and general sense of pressure and pain in the face and scalp when one coughs? No neuro symptoms, no intestinal, no body aches, and body temp very slightly below normal. One more possible clue: person used a Triclosan-containing toothpaste for about three weeks prior to onset (discontinued after onset), and developed a minor swelling in a gum a few days before onset that went away in a day or so.

    Report from a local ER: Highland Hospital, Oakland CA, a week or so ago: waiting times of EIGHT TO SIXTEEN hours from intake at about 7PM. It would be interesting to see what they do if BF hits. And this is a teaching hosp with an excellent reputation re. trauma care (yes, with all the drunk driving accident and gang gunshot cases rolling in accompanied by Sheriff’s deputies as well as EMTs).

  18. #18 revere
    February 20, 2008

    no thanks: Impossible to make a diagnosis this way, so it could be flu or a local infection or something else. Interestingly, I saw my doc yesterday and asked him if he has seen a lot of flu and he said no, exactly one case. This is a busy practice in an area where flu is said to be widespread. So it is quite spotty.