Flu iceberg no surprise

There is a puzzling newspaper report by Elizabeth Rosenthal in today's New York Times.

Two young brothers, ages 4 and 5, who have tested positive for the dreaded A(H5N1) avian virus but shown no symptoms of the disease were being closely watched at Kecioren Hospital here on Tuesday. Doctors are unsure whether they are for the first time seeing human bird flu in its earliest stages or if they are discovering that infection with the A(H5N1) virus does not always lead to illness.

In any case, the highly unusual cluster of five cases detected here in Turkey's capital over the last three days - all traceable to contact with sick birds - is challenging some of the doctors' assumptions about bird flu and giving them new insights into how it spreads and causes disease. Since none of the five have died, it is raising the possibility that human bird flu is not as deadly as currently thought, and that many mild cases in Asian countries may have gone unreported. (NYT)

I doubt many knowledgeable flu people are at all surprised by this. This is what one always sees with influenza. The proportion of asymptomatic cases of influenza infection varies in the literature but is quite high. Fukuda and his colleagues say in their chapter on Inactivated Influenza Vaccines (Ch. 17 in Plotkin and Orenstein's Vaccines, 4th ed., p. 339) that approximately 30% to 50% of infections are asymptomatic. Mutsch et al. looked at almost 1500 travelers to tropical and subtropical who filled out questionnaires and provided paired serum samples, one before departure and one on return. Out of 40 people who seroconverted (i.e., showed evidence of infection during travel), thirteen had no fever. Thus for "regular" (seasonal) influenza infections, more than 30% of the infections are without symptoms, according to these sources.

Nor is it unheard of in human avian influenza. From a CIDRAP report by Robert Roos, dated March 9, 2005:

Two relatives of avian influenza patients in northern Vietnam have tested positive for the virus without being sick, according to reports from Vietnam today.

The 61-year-old widow of a man who died of avian flu in late February and the 80-year-old grandfather of two patients currently under treatment in a hospital have tested positive, the Associated Press (AP) and other news services reported. Both are apparently healthy.

Both people live in Thai Binh province, where five other avian flu cases have been reported in the past 2 weeks.

[snip]

The confirmation of asymptomatic cases implies that infections may be more common than previously thought and that the case-fatality rate may be lower. The fatality rate for officially confirmed cases has hovered in the 70% range.

Thompson commented, "The CFR [case-fatality rate] had to be overstated. The cases we were sure of were those which were sick enough to go to a hospital and these extreme cases have very poor outcomes. Surely others were infected and either not getting sick or not getting sick enough to seek treatment at a hospital. Factoring those into the CFR has been impossible. We simply don't know the denominator." (CIDRAP)

The NYT report also notes the paper by Thorson and colleagues in Archives of Internal Medicine we discussed in an earlier post. That paper suggested many mild or inapparent infections with H5N1 in Vietnamese in the spring of 2004. This is something we and others have been saying for almost a year (for example, see this, this or this). WHO has also alluded to this earlier.

While Rosenthal's NYT article is headlined Scientific Puzzle: Some Turks Have Bird Flu but Aren't Sick, the puzzle, if there is one, is a generic puzzle about the variability of the human response to infections, in particular viral infections with influenza virus. It is not either a new or surprising finding about H5N1 infections. On the contrary, it suggests that this virus conforms to the general characteristics of infection with influenza viruses, with most of the infections beneath the clinically severe surface and many completely asymptomatic.

Unfortunately even the small tip of a pandemic influenza iceberg that sticks above the water is nasty and could case the global passenger line to founder.