More on influenza-related issues

March 2004

It occurred to me that there has been more editorial ink spilled over these topics in the last four to five months than I recall seeing in many years. Perhaps that is simply a reflection of my reading habits more than anything else. Nonetheless, at the risk of turning some readers away who may be weary of this topic already, I have yet a few more words to say on this group of vexing diseases. If we are lucky, that will conclude thoughts about influenza for the balance of the 2003-2004 season.

The outbreak of A/Fujian influenza that we and much of the Northern Hemisphere experienced in the last four months seems to be just about over. It has been an unusual epidemic in several respects: It started quite early, and was well underway by the first week of November. It has run its course quite early as well, and all indices of influenza activity, except for the excess mortality indicator, ie, the proportion of deaths due to pneumonia and influenza, had returned to baseline by the end of February. It is most unlikely that we will see a “second wave” of A/Fujian influenza this season, as was seen with Asian influenza in 1957-1958, although it is still possible that we might see a small “herald wave” of spring influenza, most likely due to influenza B, but there has certainly been no indication of such an event yet. Finally, the outbreak seemed a little unusual in its intensity in children, and the fact that deaths in children occurred and were widely publicized. The widespread media coverage resulted in a run on influenza vaccination in December, and the spot vaccine shortages that developed. It should be noted, however, that deaths in children, even in children not known to be “high-risk,” is nothing new, and these occur almost every year there is an influenza A/H3N2 outbreak. Perhaps this was the result of what I thought was unusually intense media coverage this year.

The media also became interested in vaccine composition, and why the FDA Vaccines Advisory Committee failed to put the A/Fujian strain in the vaccine. I, as well as other members and consultants of that committee, spent many hours on the telephone or actually being taped to carefully explain what had happened, why there was no A/Fujian vaccine candidate strain available last year, and why we weren’t simply being totally derelict in failing to see what would happen this year. We were all fearful that things would evolve precisely as they did, but there were simply no alternatives available at the time.

One of the favorite media questions for the “experts” was always “how effective do you think the vaccine will be?” My stock answer was always that, judging by prior experience in years when there was not a good match of vaccine strain and wild strain, this year’s vaccine would likely prove to be from 40% to 60% effective. CDC, being under intense pressure to answer that question, made a valiant effort to do so at Children’s Hospital in Denver, and published the results in the Morbidity and Mortality Weekly Report in January. The observed efficacy was zero, though the confidence limits were enormously broad. It was a valiant effort, but the retrospective questionnaire study design was so seriously flawed that no believable data could be derived. More recent data from the armed services, from countries in Europe, and most recently also other data from CDC are assessing efficacy in the 40%-60% range, so my prediction seems to have been more or less accurate.

The FDA Vaccines Advisory Committee and consultants met again in mid-February to review the current status of epidemic influenza globally, and to begin to decide the composition of the 2004-2005 vaccine. The prevailing mood was sharply different from a year ago, for this year there were no hidden surprises and no suggestion that any new threat was about to emerge, at least as concerns human influenza viruses. Consequently, decisions about candidate strains were relatively easy to make.

Briefly, there is nothing really new among the A/H1N1 strain, so that strain will remain the same as in the 2003-2004 vaccine. There are now several good A/H3N2 Fujian-like strains available for vaccine production, and since there has been little further antigenic drift among these strains, an A/H3N2 Fujian-like strain will replace the current A/H3N2 Panama strain.

Influenza B strain choice

The most interesting problem was the choice of influenza B strain. For about 15 years there have been two distinct lineages of influenza B circulating in the world, one known as the B/Yamagata lineage, and the other as the B/Victoria lineage. These two lineages have waxed and waned in frequency of isolation over the years, and B/Victoria-like strains have been in the ascendancy for the past five to six years. Now it appears that is changing, and the B/Yamagata-like strains are again circulating more broadly. The committee recommended that a change be made to a suitable B/Yamagata-like strain, with the understanding that there will be one further opportunity to review this decision in mid-March.

So much for human influenza viruses.

Avian influenza viruses received a great deal of attention. A current outbreak of a highly pathogenic avian influenza virus in Texas is causing perhaps the greatest concern (read the article). See also the article from our Thai correspondent, Kulkanya Chokephaibulkit, to gain an appreciation of the impact of avian influenza on one Thai family, and the resulting threat to Thailand, to neighboring countries and to the world (read the article).

The New England Journal of Medicine electronically published an article by T.T. Hien and others, describing avian influenza A/H5N1 in 10 patients in Vietnam that were identified in January 2004. This article will appear in print in the March 18th issue. The 10 patients were all children and young adults, mean age 13.7 years. The oldest patient was 24. They lived in seven different locales in Vietnam. Dates of onset of illness were late December 2003 or January 2004. All patients either lived on farms with chickens, or otherwise had close contact with chickens. No evidence could be found of human to human transmission. The disease appeared to be quite severe, with fever at presentation of 38.8° C to 40.0° C, respiratory symptoms, significant lymphopenia and often thrombocytopenia as well. Seven patients had diarrhea. Eight of the ten patients died.

This reported outbreak, including the stunning mortality rate, does not differ appreciably from those reported previously, particularly in Hong Kong in 1997 and 2001.

Thus, the great concerns expressed by epidemiologists, virologists and public health officials seem to be thoroughly justified. If a recombination event occurred in a person co-infected with a human influenza virus, and an H5N1 recombinant possessing the ability to spread from human to human emerged, would it really be 1918 all over again, as some have predicted? The answer appears to be clearly yes.