WHO formulates ambitious avian influenza pandemic response plan

April 2006

In the past four to five months, avian influenza has spread dramatically from several foci in southeast Asia to all of Asia, parts of the Middle East and eastern Europe, several countries in Africa and Scandinavia, and may soon involve France and the British Isles. All this has happened presumably on the wings of migratory birds, although a vocal minority also cites the possible importance of illegal trans-shipment of infected poultry.

It seems only a matter of time before infected birds are found in North America. The spring bird migration season is upon us now, but that comes primarily from Central and South America and the Caribbean. If it doesn’t happen this spring, it may very well happen in the fall when migratory birds from Alaska and perhaps northeast Asia migrate south.

Concomitant with this rapid and dramatic spread in poultry and avian species, there has been an increase in cases in humans; there are now about 200 confirmed cases and over 100 deaths. To date, however, almost all of these cases have been traced to contact with sick or dead birds or poultry, and sustained human-to-human transmission has not yet occurred; at least it has not yet been recognized.

The threat

Faced with the obvious threat of mutation of the avian H5N1 virus into a form capable of being transmitted efficiently from person to person, WHO has put together an exceedingly ambitious pandemic influenza draft protocol for rapid response and containment. It is now in its second draft, and was released on March 17, 2006. Interested readers can find it on the WHO Web site at www.who.int/csr/disease/avian_influenza/guidelines/pandemicfluprotocol_17.03a.pdf.

I will try to summarize this draft plan in the comments that follow, but one almost has to read the entire document to appreciate the scope of what is being proposed.

There are two major components in the plan:

• Signal or event detection, investigation, reporting and verification; and
• Containing the event to include two levels of response: standard measures to reduce transmission and exceptional measures including use of an antiviral stockpile.

Signals or events include both epidemiologic and virologic signals. WHO has proposed that clusters of three or more people with unexplained moderate-to-severe respiratory illness with onset within seven to 10 days of each other, coupled with a history consistent with the possibility of exposure to an infected avian source or a known or suspected H5N1 patient, be investigated for evidence of infection caused by a novel influenza A virus.

Virologic signals might include detection of a virus with both human and avian genetic material, suggesting a possible reassortant virus, or the isolation of a virus from a human case showing a number of mutations not found in avian isolates.

Either or both signals should result in prompt virologic or epidemiologic investigation, verification and reporting to national health authorities and WHO. Immediate measures recommended by WHO include:

• Isolation of clinical cases;
• Identification, quarantine and monitoring of exposed contacts;
• Antiviral drugs for treatment of cases and targeted prophylaxis;
• Strict infection control and use of personal protective equipment in health care facilities;
• Intensively promoting hand and respiratory hygiene; and
• Domestic cleaning to reduce transmission through fomites.

The WHO plan goes further, however, and attempts to contain an emerging pandemic virus at its source. The first level of the containment response is to be activated under these criteria:

• Moderate-to-severe influenzalike illness in three or more health care workers who have no known exposure except for contact with ill patients, and isolation of H5N1 in at least one health care worker;
• Moderate-to-severe influenzalike illness in five to 10 people, with evidence of human-to-human transmission in at least some of them, with virologic confirmation;
• Strong evidence that more than one generation of human-to-human transmission has occurred; and
• Isolation of a novel virus containing an increased number of mutations not seen in avian viruses, with epidemiologic evidence that transmission patterns have changed.

The major features of the first level containment response include active surveillance, contact tracing, targeted antiviral chemoprophylaxis, monitoring of contacts, infection control in health care facilities and, of course, individual case management. These measures must be implemented ASAP. The draft proposal states that mathematical modeling studies have shown that this approach has a chance of success only when antiviral drugs are administered within three weeks following detection of the first case.

Failure of the phase-1 strategy, or a more extensive signal event, should prompt consideration of moving to the phase-2 strategy, which includes everything in phase 1 plus more extensive quarantine and monitoring, implementation of “social distancing” measures and mass use of antiviral drugs, specifically oseltamivir (Tamiflu, Roche).

The remainder of the WHO document is devoted to an outline of responsibilities, and which authorities are responsible for various components of the plan, ranging from local, national and eventually international agencies. WHO will also train a number of “rapid response teams” that could travel to virtually any part of the world where a signal event had been recognized. The plan surely will stand no chance of success unless there is a high level of international cooperation working to achieve a common goal; realistically, there can be no guarantee of that among all the countries of the world. Moreover, the intensity of surveillance varies widely in different parts of the world, ranging from generally good in developed countries to virtually non-existent in some undeveloped countries. It is possible that a pandemic signal event could escape detection until the pandemic virus had already spread too far to consider containment.

This is a hugely ambitious, very resource-intensive and wholly untried on an international level proposal. Keiji Fukuda, MD, MPH, acting director of the WHO global influenza program, his staff and international advisors put it together. Fukuda had spent the previous decade or more in the CDC influenza program; indeed, there are many analogies between the WHO proposal and the CDC’s influenza control activities.

Could a plan like this succeed in containing an emerging pandemic influenza threat at, or close to, its source? Skeptics abound, of course, but on the other hand, never before have we been in a position that a plan like this could even be considered. Even if an emerging pandemic can be contained for only a short while, perhaps several months, it would still buy some time to devote to vaccine production. Thus, it’s well worth trying.

I applaud the boldness of the WHO plan, and at the same time, I hope that it never needs to be implemented.