The best summary of H5N1 to date

This week The New England Journal of Medicine (NEJM) published three articles on the evolving story of the influenza A/H5N1 panzootic that has the potential to become a human pandemic. Two are rather meager case series, one from Turkey and one from Indonesia. It is an extraordinary indication of the paucity of information that these papers could get published in one of the world's premier medical journals, a fact duly noted by Canadian Press's Helen Branswell. The two papers have some moderately interesting information, none of it startling for those who follow this issue. But the Commentary by Robert Webster and Elena Govorkova that accompanies the two papers is a model of clarity and a stunning summary of where we are at this moment. Hardly a word of the 1600 word essay is wasted. It would make an admirable blog post. Here are the opening and closing paragraphs:

There is no question that there will be another influenza pandemic someday. We simply don't know when it will occur or whether it will be caused by the H5N1 avian influenza virus. But given the number of cases of H5N1 influenza that have occurred in humans to date (251 as of late September 2006) and the rate of death of more than 50%, it would be prudent to develop robust plans for dealing with such a pandemic.

[snip]

Clearly, we must prepare for the possibility of an influenza pandemic. If H5N1 influenza achieves pandemic status in humans -- and we have no way to know whether it will -- the results could be catastrophic. (Webster and Govorkova, NEJM)

Everything sentence between these two paragraphs is a gem and the whole summarizes the history and essential points in the rapidly moving science of H5N1. Here is a paragraph, taken more or less at random to illustrate the point:

The H5N1 viruses can be divided into clade 1 and clade 2; the latter can be further subdivided into three subclades. The bad news is that these clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines. Studies in ferrets suggest that vaccine against one clade will not protect against infection with another clade, though it will protect against influenza-associated death. Thus, the available information supports the notion that a vaccine against H5N1 is worth stockpiling as a "prepandemic" vaccine, since very few persons have been immunologically exposed to H5 antigens and priming with one clade may be beneficial.

The amount of information packed into these four sentences is remarkable. If you want a quick overview of the state of the science at this point, this is the proverbial "must read."

The other papers are small but useful additions to what we know, mostly, as I have said, because almost any detailed clinical description of cases adds a proportionately large amount to a minute literature.

The paper from eastern Turkey reports on eight cases, aged 5 to 15 years old, all of whom gave a history of close contact with diseased or dead chickens. The human cases followed a major poultry outbreak in the area. In none of the cases was there a positive rapid test for influenza A and there were also 8 negative RT-PCR results, only later followed by the positive RT-PCR results that made the diagnosis. Thus H5N1 infection remains difficult to diagnose in the average laboratory or clinical setting. All patients presented with fever, and cough and sore throat were present in most. In common with the Indonesian patients, almost all presented with x-ray evidence of pneumonia involving both lungs. Three cases had bleeding gums and three had diarrhea. Neither of these presenting symptoms were reported in the Indonesian patients. No bacterial infections were reported in either case series.

The Turkish patients were among a total of 625 who came under suspicion and were seen at the authors' hospital, although the reasons for the referrals weren't given. 21% of these (131) had a history of contact with poultry and were given prophylactic Tamiflu as outpatients. Another 25% (159) had influenza-like illnesses along with their history of poultry contact. Eventually ten were diagnosed as having H5N1 infections by RT-PCR although the WHO reference laboratory confirmed only eight. These eight had a median age of 10 years (5 - 15).

The authors make two very important observations:

Many of these patients' siblings and parents also had contact with diseased poultry in the home but remained healthy, suggesting that the intensity and duration of contact with infected birds may be important in transmission. (Oner et al. NEJM)

And this:

As in the cases reorted by Kandun and colleagues [the Indonesian paper, discussed next], the rpaid influenza antigen test did not detect H5N1 infection in our atients. We were ablt to diagnose H5N1 infection because of a high index of suspicion during a known epidemic of this infection in poultry and because all the patients were seen at a regioinal referral center, were fro ma small geographic area, and had similar clinical presentation. Thus testing was repeated.

The second point underscores how likely it is that human cases are missed. A continual concern with vaccinating poultry is that it will mask H5N1 outbreaks in bird flocks and thus lower the index of suspicion. The first observation that we don't know why some people get sick and others, seemingly similarly exposed do not, is important, but the reasons given (differing intensity and duration of exposure) are just speculation at this point.

Half of these Turkish patients died. The sublineage or clade of the isolated viruses was not determined. The Indonesian paper, on the contrary, describes three small clusters that occurred before the large Karo cluster that raised so much alarm. The virus was shown to belong to clade 2 was sensitive to both classes of antivirals (M2 blockers and neuraminidase inhibitors). There are some similarities and some differences between these cases and the Turkish ones. Fever and bilateral pneumonia again were the primary presentations but no reports of bleeding gums or diarrhea. Lowered albumin and elevated enzymes that may be associated with liver damage were seen in both countries but there are other explanations for these findings as well. Possible involvement of the liver is a new feature that should be examined further and suggests the gastrointestinal tract is a more important portal of entry than previously given credit (this is our inference, not the inference of the authors).

Unlike the Turkish cases, history of direct contact with diseased poultry is mainly absent, although there are reports in some instances of sick poultry "in the area" of the case. The Indonesians have been unusually resistant to any suggestions there is a vector of H5N1 other than poultry. In these cases they are quick to invoke "environmental contamination" with material from sick poultry (dust, feathers, feces). This may or may not be correct. The suspicion there are other modes of transmission and possibly other reservoirs remains a matter of concern not dispelled by these more detailed reports. We still await a description of the eight person Karo cluster that occurred after these cases, for which person-to-person transmission seems the only plausible explanation. This paper has been around in draft form for quite a while and it isn't likely it presents much new information to those specializing in this area, although it is useful for a general medical and scientific audience.

All three papers are publicly available at the NEJM website (at the links given, above), which is usually subscription only. We applaud The Journal for the increasingly common practice of making H5N1 scientific papers Open Access.

And no matter what your state of knowledge or prejudices about whether avian influenza is or is not a current threat, read the Commentary by Webster and Govorkova. It is a masterpiece of summarization.