Influenza: The 2002-2003 season

May 2003

The 2002-2003 influenza season is all but over, and we are seeing simply the tail end with widespread activity in only one state — Alaska. It was a mixed year, with both influenza A, mostly A/H1N1, and influenza B circulating.

Although there were many reports of increased school and workplace absenteeism from influenza, there was no excess influenza-associated mortality. The absence of excess mortality was the direct result of the relative absence of influenza A/H3N2 disease. All in all, it was a generally benign year, with no major unpleasant surprises (except for Severe Acute Respiratory Syndrome, of course), and a good match between the circulating strains of both influenza A/H1N1 and influenza B and the production strains of each used in preparing the 2002-2003 vaccine.

This salubrious state of affairs is unlikely to continue much longer, and already there are some warning signs that suggest that change might be coming sooner rather than later. More on that later.

Several interesting and relevant studies were published during the last year that further illuminate considerations of influenza-associated mortality, vaccine safety and efficacy, and new respiratory disease agents that may to some extent mimic influenza. An example of the latter is the gradually growing body of knowledge about the epidemiology of human metapneumovirus infection. A good starting point for readers who wish to learn more about these recently described agents is the report of Falsey, et al (JID. 2003;187 (March 1):785-790). It is not yet clear whether these viruses are capable of causing true outbreaks or epidemics, but they must clearly be considered now in the differential diagnosis of influenza-like illness in adults and the elderly, together with parainfluenza viruses, respiratory syncytial virus (RSV) and Chlamydia pneumoniae.

Mortality increasing sharply

In the Jan. 8, 2003 issue of JAMA, CDC investigators reported that influenza and RSV-associated mortality had increased sharply in the United States during the time beginning with 1976-1977 to the 1998-1999 season. This increase was seen in three major mortality categories: underlying pneumonia and influenza, underlying respiratory and circulatory diseases, and all cause mortality. Although the increase is difficult to express quantitatively, the authors speculate that influenza-associated mortality rates have approximately doubled in that period. Instead of the 20,000 to 40,000 excess deaths each year that we heard about 20 years ago, today a figure of 50,000 to 70,000 would be more accurate. This increase is due in large part to the steadily aging U.S. population. Also striking was the share of mortality attributed to RSV — overall about one-quarter of the total mortality. Certainly, influenza was the major culprit, yet, the increased prominence of RSV-associated mortality was surprising.

Regarding vaccine efficacy, the contributions of Dr. Kristin Nichol at the VA Medical Center in Minneapolis and her co-investigators have been particularly valuable during the last five to seven years. Their most recent contribution (NEJM. 2003;348:1322-32), again using large linked databases, was a demonstration that influenza vaccination resulted in an approximate 20% reduction in hospitalizations for heart disease and stroke among the elderly, as well as a reduction in all-cause mortality during influenza seasons (See related story.). The figure of 20% was across several seasons, and there was some year-to-year variation depending on which viruses were circulating, the vaccine composition, and the like.

A curious vaccine safety issue was well described in two recent publications from Canada (1. Skowronski, et al. CID. 2003;36 15 March. and 2. Schiefele, et al. CID. 2003;36: 1 April) The Oculorespiratory Syndrome (ORS) was first described during the 2000-2001 season, and consisted of conjunctival redness, facial swelling of the eyelid, lip, or mouth, and some respiratory symptoms such as sore throat, hoarseness, difficulty swallowing, wheezing, and the like, all with onset within two to 24 hours after immunization and fully resolved within 48 hours after onset.

This appeared to be uniquely associated with influenza vaccine produced by one Canadian manufacturer. Although the features of ORS suggest “allergic” components, and appear to involve an as yet undefined immunologic mechanism, the implicated vaccine was otherwise minimally reactive. Initial electron microscopic observations suggested that the vaccine contained large clumps of unsplit virions, particularly involving the influenza A/H3N2 component; the significance of this observation is not yet clear. Although most of us in the United States have not seen ORS in vaccinated patients, it is clearly something to which we need to be alert.

Other developments

In an apparent natural re-assortment event, an influenza A/H1N2 strain emerged several years ago in Europe, and has continued to circulate in relatively low numbers. It behaves epidemiologically much like influenza A/H1N1, and is in fact indistinguishable from that parent virus except by antigenic characterization. It was widely prevalent in the Untied States this year and fully protected against by the influenza A/H1N1 component in the vaccine.

Medicare reimbursement rates for influenza vaccine were almost doubled!

A major U.S. manufacturer, Wyeth, announced that it would no longer produce inactivated influenza vaccine, but instead place its entire emphasis on the as yet unlicensed cold-adapted, intranasal influenza vaccine (FluMist). This has created the possibility of additional shortages of inactivated vaccine in the fall of 2003.

There has been continuing intermittent spread of avian influenza viruses into humans, but as yet no known sustained human-to-human spread. Two human cases of influenza A/H5N1 occurred in Hong Kong several months ago, in a family that had recently visited Fujian Province in China. There is no available information on possible additional cases due to this virus in China. Very recently, there have been reports of influenza A/H7N7 disease in poultry, pigs and humans in the Netherlands. Thus, the CDC is on a continuing alert for transmission of these and other avian influenza viruses to humans.

What should we expect?

What of the 2003-2004 season? In the last half of the 1990s, we experienced an unprecedented four consecutive years of epidemic influenza A/H3N2, each one with major excess mortality. The last three years have been something of a reprieve. There was influenza A/H3N2 disease during the 2001-2002 season, to be sure, and there was some excess mortality, but it was not of the scale we experienced in the 1990s. Hence, this observer would not be at all surprised if we again experienced a major A/H3N2 outbreak.

The vaccine for next year is unchanged from this year’s vaccine. In over 25 years of participating in the vaccine-strain selection process, this is one of the few years in memory in which no change in vaccine composition was made. It is not because of enough information; to the contrary, the amount of global influenza surveillance information available is better than ever before!

Rather, it was due to the absence of satisfactory candidate strains. I am referring specifically to the A/H3N2 component. There is a group of these viruses circulating that show reduced titers to ferret antisera produced against the vaccine strain; thus, they are somewhat poorly inhibited, and likely less well protected against by the current vaccine. It is possible that these A/H3N2 strains might emerge to become predominant next year, and for several technical reasons, a suitable candidate strain was simply not available for vaccine production. Thus, the FDA vaccines advisory committee was confronted with a “Hobson’s choice.” Wait longer, and risk a high probability of major vaccine shortage, or retain last year’s strain, and risk the possibility of a less than optimal level of protection. Obviously, the committee chose the latter.

For the first time in many years, many of us were distinctly uncomfortable about the prospects for the 2003-2004 influenza season.