Part III on Influenza: What it is not. An anti-definition

It is the negative definition of flu that concerns me.

At its core, influenza is not a simple disease. From an evolutionary standpoint, it's pretty damn elegant and efficient. And complex.

There is a lot that is understood about influenza and its method of evolving, infecting, and persisting. But a huge part remains unknown. For instance, scientists have discovered the "how" of influenza infection, but they are still working toward understanding what actually happens to the human system when influenza infects it.

This surprises me. When I first learned this, I was amazed that that science hadn't answered this long ago. But there are countless mysteries that remain about the human immune system, its response, and the exact process of many diseases.

A particular mystery of flu is why certain cases of influenza have such horrible systemic complications. These complications, usually involving lungs and circulation, can arise rapidly from flu. These are the most troubling, and the most fatal. There is a point of no return when a flu turns aggressive, and the mystery is often this: it is impossible for a doctor to determine at the beginning whether a specific case will involve these complications or not. This is true even with seasonal flu, but predicting outcomes is even more difficult with a novel influenza.

Before you stop reading and accuse me of being alarmist, let me clarify that in terms of percentages, there is still certainly every reason for to most cases of influenza infection to resolve without any serious complications for the patient. Most people who get flu--seasonal or even pandemic flu--recover without a problem.

The numbers are more complicated than they seem, though: To talk about the scenarios of infectious disease is to talk about variables. The outcome of each case is based a whole set of variables, some of which are unknowable. In a regular season of influenza, some of these variables are better understood. For example, a person with a weaker immune system (think of an elderly or immunocompromised person) will tend to be more at risk for a severe case.

With a novel influenza, the scenario is sufficiently different. There are several new considerations, each which influences the potential for poor outcomes:

First, with a novel influenza, the number of people who get sick is much larger than it is in a regular year with "seasonal" flu. This year, some projections from the CDC estimate that up to 60% of the population in the US will be infected with the virus. This is vastly different from the estimated number of people who get flu in a regular season, which caps at around 20%. More people getting sick means more potential outcomes. That's the first variable.

The second consideration regards who is getting infected. A novel influenza affects entirely new groups of people, people who usually aren't as vulnerable to infection in general. 2009's H1N1 is hitting young adults and healthy children pretty hard. The elderly, who are usually the most vulnerable, are not getting this flu in the same numbers as the younger people in our population. There is some speculation that some older people may have been exposed to some element of the older genetic material of this year's H1N1, and that is making them slightly less likely to get infected. With that said, though, when the elderly do get it, they are quite sick--and they one of the larger groups hospitalized for complications related to flu this year.

A particular variable that concerns me regards the elusive nature of flu as a virus. Consider these points:

• Flu is a common illness, but--surprisingly--it's often an unknown quantity. It's not always easily diagnosed at the bedside, as there are a whole host of "influenza-like" viruses. The symptoms of flu can vary widely from person to person, from something that resembles a cold, to something closer to pneumonia. In particular, this flu is presenting with *no* fever in some people. This, again, makes it trickier to diagnose. Even a test for that's done at a doctor's office is not 100% reliable for determining if the patient has flu.

• There are several types of rapid tests used in clinics, but they all operate in mainly the same way: they detect influenza viral nucleoprotein antigen. To put it simply, the rapid tests search the sample for elements of protein from the influenza protein. What these tests can't do is determine specifically which subtype of flu a patient has. Unfortunately, samples vary, and not everyone who gets these rapid tests gets an accurate result. The CDC advises clinicians that they should not rule out flu based on this test because there is a possibility of a false negative (the test says no flu, but you actually do have it). And again, there are false positives, as well. The tests that do the actual subtyping of flu are the ones done by the CDC and by state health departments, and these are accurate, but expensive, and time consuming.

• Flu is constantly using several mechanisms to adapt itself. Antigenic drift is happening all the time with flu. The flu circulating now will not be the flu that circulates next year, or perhaps even at the end of this flu season, in the spring. That constant change just adds to the uncertainty.

All of this--these variables, this shifting, these spaces in understanding--it all indicates flu is nothing if not more complex than it seems.

Which brings me to the next definition of what influenza is not: It's not "just flu." Though it may be a common ailment, it shouldn't be taken casually. It teeters on that edge of dangerous, even in years of regular old seasonal flu. A novel influenza, such as this year's H1N1, falls off that edge into dangerous territory more often.

Because it is a new virus, with genetic components from avian, swine, and human influenza, this year's H1N1 seems to have triggered a very, very robust immune response in some people, especially healthy young people. Pregnant women also have a huge immune response. Unfortunately, there is a limit to what good that robustness can do. There is some speculation that, at some point, the immune response can actually overwhelm to the body, creating what is called a cytokine storm. Think of it as too much of a good thing. One theory about the cytokine storm is that it creates a sort of "feedback loop" among the antibody response, and that this contributes to the collapse of the respiratory and circulatory system.

There is a lot of work being done on this topic right now, and here is an excellent explanation of what a cytokine storm is, and some great discussion of the topic in general, if you are interested. While the jury is out on the exact mechanism of the cytokine storm and how to mitigate it, it certainly seems to be present in the worst cases of influenza infection. Whether the cytokine storm is a cause of death, or a result of the infection itself--this remains unknown. At this time, cytokine storm remains one of the mysteries about influenza infections, but once understood, this knowledge might make a huge difference in changing the outcome of severe cases.

In 1918, the pandemic was caused by a novel H1N1 influenza. The numbers of people affected with serious or fatal cases was (fortunately for us) much higher than what we are seeing with the H1N1 circulating this year. But there are certainly similarities in the populations who seem to be having the most severe cases. Pregnant women and young adults suffered disproportionate numbers of complicated cases in 1918. And this year, pregnant women and young adults seem particularly vulnerable to influenza infection, and more likely to suffer complications once ill. With all that is unknown about influenza, this much seems clear: this year's novel influenza is more dangerous to more people than a seasonal flu.

And that's why my alarm bell has started ringing...

Some more about that, and the personal reasons this might be affecting me, in the next post.

♦DiggIt! ♦Add to del.icio.us ♦Add to Technorati Faves