Effect Measure

Red wine has been touted for its health benefits but these don’t seem to extend to warding off swine flu. The virology laboratory in Bordeaux in the southwest of France tested via RT-PCR over 1200 nasopharyngeal swabs between May 1 and the first week in October and found 186 positive for the new pandemic strain. They looked at five of these cases more closely, monitoring them for duration of viral shedding. Two of the five kept shedding for 2 to 4 weeks (paper in Eurosurveillance by Fleury et al., v. 14, #49, December 10, 2009).

The first case was a non-obese previously healthy male in his mid fifties. Shortly after returning to France from California in the beginning of July he developed fever and had difficulty catching his breath. Within a day he was in the intensive care unit. A swab was positive for the presence of the swine flu virus. He was started on the recommended dose of oseltamivir (Tamiflu, 150 mg daily) and improved rapidly. He was soon transferred out of the ICU, but repeat swabs showed he was continuing to shed virus. Oseltamivir was continued and then changed to zanamivir (Relenza). He continued to shed virus for another 7 days, until day 15, when he was discharged. He was evaluated for immunosuppressive illness and found not to have any signs of one.

The second case was a morbidly obese (BMI over 50) woman in her late twenties, just returned from Spain in late July. She had flu-like symptoms for 5 days while at home but began to deteriorate and wound up in an intensive care unit on 31 July. A nasopharyngeal swab revealed the presence of the virus and she, too, was started on oseltamivir at the recommended dose. Her conditioned worsened and she developed acute respiratory distress syndrome (ARDS) and was put on a ventilator and then extracorporeal membrane oxygenation (ECMO), essentially a heart lung machine that allows the blood to get oxygen without requiring the lungs to work. Oseltamivir was increased to a double dose (300 mg per day) on 2 August. Her condition allowed deep respiratory secretions to be obtained and they remained positive for the virus for 13 samples (19 days). Of interest was that nasopharyngeal swabs were negative when deep lung secretions were positive in this patient. Virus continued to be detected until day 31 after symptom onset. Miraculously, this critically ill woman with a major risk factor made a full recovery and left the hospital at the beginning of September. She, too, was evaluated for immunosuppressive conditions but no sign of one was found.

What about the virus? These patients were treated intensively with the antiviral neuriminidase inhibitors but had prolonged viral shedding, although both did well clinically. The viral isolates were checked for the main mutation that confers resistance (H274Y) and neither had it. The virus was apparently sensitive to the drugs. So there was no apparent explanation for why these patients continued to shed virus for much longer than the usually claimed period of 5 to 7 days from onset. This was despite the use of antivirals which in experimental challenge studies with human volunteers have cut the length of viral shedding in half (a median of 107 hours to 58 hours). Prolonged viral shedding can occur in children and the immunocompromised, but that describes neither of these patients.

There is data on viral shedding in influenza but not a great deal of it. Our guess is that the previous estimates, based on rather small samples, do not adequately account for a substantial number of prolonged shedders there might be when millions of people are infected. Even if prolonged shedding occurs infrequently, say in one in a thousand cases, this could still produce thousands of people who continue to shed influenza virus for weeks after they are apparently recovered.

It may be that people can continue to harbor infection and even shed virus to some extent, but not enough to infect others. It’s another of the many things we don’t know about flu. But now we know that prolonged shedding of virus can and does occur. We just don’t know what it means.

Comments

#1 anon
December 13, 2009

2 out of 5, as I understood, not one in thousand ?
#2 revere
December 13, 2009

anon: They checked 5 for length of viral shedding and two had prolonged shedding. We don’t know what the actual rate of prolonged shedding is, but the point I was trying to make is that even if it is quite rare, say one in 1000, with millions infected that’s quite alot of prolonged shedders. Maybe it’s even rarer or more common. Either way, we don’t know what it means, but the idea that shedding is limited to 5 to 7 days may or may not be a good working assumption.
#3 Epifreak
December 13, 2009

PCR can pick up dead DNA so a person who is PCR positive might not be shedding live virus. It would be interesting to know if these patients would have been culture positive.
#4 revere
December 13, 2009

Epifreak: I rather suspect that there’s too much degradation going on in those tissues to expect that the detectable viral RNA is just hanging around for 2 – 4 weeks without continuous generation. I may be wrong, but I think their interpretation that this is continued viral production is quite correct. There was no mention of attempts to culture.
#5 SusanC
December 14, 2009

Do you get a sense that this may go with the severity of illness? Both of these patients needed intensive care. Are we seeing any prolonged shedding in patients with mild or no symptoms?

Second thing that comes to mind, patient #2 was extremely obese and didn’t start oseltamivir till day 6. Is there a case for giving patients with severe disease and/or high BMI, a higher dose to start with? Especially with someone who presents late. The 150mg/d dose is the standard dose indicated for uncomplicated influenza in normal healthy patients. We are back to the same old question, of inadequate dosage/efficacy information on use for higher risk patients, more severe cases, or simply someone who has double the body weight of the ‘average’ person.
#6 revere
December 14, 2009

Susan: I don’t think we know that much about the length of viral shedding or the length of viral infection/replication in most cases. It has been studied in volunteers but not that much in community cases. Note that the first case improved clinically very rapidly but continued to have replicating virus in the deep lung but not np swab. How often does that happen? I don’t think we know.
#7 melbren
December 14, 2009

Is there any research about the possibility of some people being “reservoirs” for influenza? (Carriers?) For example, Revere has mentioned that we are not entirely sure where the seasonal flu hangs out during the off-season (Vero Beach?) But is it possible that some people just walk around with sub-clinical levels of the influenza virus much of the time?

Looking back on things, I wonder if my daughter may be somewhat of an “epidemiological trend setter.” I always noticed that, although she became quite ill several times each year as a child, she never seemed to become ill with whichever “bug that was going around” in her community. Now I am wondering if the bugs that start going around in her immediate community, begin to do so a week or two after she gets the party started.

Could it be that she has certain viruses that set up shop sub-clinically in her, and then a bacteria comes along and provides her with the symptoms that she needs to pass the virus along—like a runny nose, sneezing, and/or coughing? Perhaps a solid bacterial infection acts as a triggering mechanism for the release of a latent virus?

Maybe?
#8 melbren
December 14, 2009

Furthermore, along those same lines of thought, someone like my daughter would remain immune to the virus as it worked its way throughout her community. Usually, it would self-limit in a population, because seasonal influenza would not work its way through a community too quickly due to a baseline of immunity in the human population. Seasonal influenza would not have a tremendous opportunity to mutate, so chances are, under normal conditions, it wouldn’t get a second chance to infect her. But, during a pandemic, when a population is naïve, the flu has more opportunity to mutate, so it does. If such is the case, perhaps it would stand to reason that a pandemic flu—-unlike seasonal flu– would be more likely to work its way back to people like my daughter before it died out, in a form that has evolved enough not to be recognized by their immune systems. If this were the case, perhaps people like my daughter, those who are thought to have been infected early on in the course of this pandemic, could be monitored for re-infections; perhaps such re-infections might serve to signal new waves of infection in a community.

I think my daughter had the swine flu in early March. She has had fits and starts since then, but she did not get sick enough for medication again until two weeks ago.

Full disclosure, however–I am not a doctor, I have never played one on tv, and I have never even stayed in a Holiday Inn Express. But I decided to run this past you all anyway.
#9 Murfomurf
December 16, 2009

I was surprised that there was much viral shedding after flu (although I don’t know what I based it on!) and wondered about even more prolonged shedding with viruses like the mononucleosis/glandular fever virus…it’s just that I’ve had some odd experiences after having the infection 40 years ago. Any clues, references that could fill me in?
#10 revere
December 16, 2009

murfomurf: I suspect it’s not been well studied but I don’t know.
#11 anon
December 16, 2009

the sequences show, that flu doesn’t oversummer but
is rather introduced new each season from Asia
#12 hope
December 17, 2009

I don’t know if the Swine flu is going to stay with us for a long time but I do know we must protect ourselves.
“swine flu is possibly the mildest pandemic on record”. (H1N1 news http://www.isrameds.com) But still we must be careful.
#13 matt carmody
December 17, 2009

Aren’t shore birds, like plovers, reservoirs of the seasonal flu?
#14 revere
December 17, 2009

matt: Not that i’ve ever heard. Do you have a cite? Aquatic birds carry a lot of influenza virus (birds are the natural reservoir for flu virus) but I haven’t heard they carry human adapted H1N! or H3N2.
#15 Sarah
December 24, 2009

This seems as good a place as any to interject. With the recent findings of “swine” flu in common pets (ie cats & dogs), is it possible that the next wave could be spawned by transmittal between and/or additional mutations that take place while in these other hosts? Now that it has appeared in the feline and canine populations, does this mean that there are other species that are more vulnerable to transmittal now (ie equine, bovine, etc.)?

Also can we estimate the significance of the species leap to those species that seem to be less vulnerable to human virus?
#16 revere
December 24, 2009

Sarah: With flu, you can’t be sure of anything. This virus seems unusual in its promiscuity, something we noted here and has since been commented on by others in the flu community.