Time is flying: Bird flu on wing as hospitals plan for pandemic

But human infections still rare, transmission rarer

As the nation’s hospitals scramble to implement pandemic plans, avian influenza A (H5N1) continues to wing its seemingly inevitable way toward North America in the flight of migratory birds. Those televised images of garbed decontamination teams and piles of dead chickens soon could be emanating from the United States.

"Clearly we don’t have a human pandemic, but if you are a bird, the news is getting worse and worse," said Andrew T. Pavia, MD, chair of the pandemic flu task force formed by the Infectious Disease Society of America. "If you consider the spread throughout Asia and [beyond], the arrival of avian disease in North America is highly likely to inevitable," he added.

The chief of the division of pediatric infectious diseases at the University of Utah Health Sciences Center in Salt Lake City, Pavia recently spoke in Chicago at a pandemic flu plenary session at the annual meeting of the Society for Healthcare Epidemiology of America (SHEA). Though human infection is rare and transmission between people rarer still, the scope of the panzootic outbreak in wild birds and poultry is striking. Colorful maps displayed on speakers’ slides at SHEA underscored how far-flung the virus has become in domestic and wild birds. Two distinct genetic strains or "clades" have developed, adding yet another complication to vaccine development. Clade 1 viruses are prevalent in Vietnam, Thailand, Cambodia, and Laos. Clade 2 viruses have been circulating in Indonesia and China and now are moving into Europe and Africa.

"We have seen in the last six months an expansion from Asia into Western Europe, Eastern Europe, the Middle East and now Africa," said Tim Uyeki, MD, MPH, a medical epidemiologist in the national center for infectious diseases at the Centers for Disease Control and Prevention. "We have seen perhaps an increasing role of wild birds. A lot of wild birds have died, and H5N1 virus has been isolated from them. The role of migratory birds appears to be increasing."

The arrival of H5N1 bird infections in the United States would pose an immediate threat to the nation’s poultry industry and certainly galvanize pandemic planning. But the larger question remains whether the virus will mutate and become readily transmissible between humans. Hospitals must prepare as if the answer to that question is "yes." Even though the virus is having considerable problems infecting humans, the exploding reservoir of H5N1 in the global bird population has raised the stakes considerably.

In the shadow of Katrina

Moreover, in the shadow, mold, and mildew left by Hurricane Katrina, attention must be paid to the worst-case scenario. Not only that the dreaded mutation may occur, but that the resulting virus will be as bad as its avian predecessor — the 1918 H1N1 pandemic flu strain.

"Some would say that planning for worst-case scenarios is just fear mongering, but I think the people in the lower ninth ward [of New Orleans] would suggest that worst-case scenarios do happen," Pavia said. "Planning must include the worst-case scenario, and there are reasons to think the worst case may not be completely beyond the pale here."

By way of example, Pavia cited a disturbing finding in the recent genetic construction of the infamous 1918 flu strain. Researchers reassembling the virus found it was avian in appearance but showed no signs of reassortment with another flu virus of human origin. That finding runs counter to the conventional wisdom that the H5N1 bird flu will not become transmissible in humans until it reassorts with a human flu strain.

"A piece of dogma that probably held sway for 40 years is not true," Pavia told SHEA attendees. "That dogma was that recombination must occur for genetic shift to occur. We now know that 1918 H1N1 was a derivative of what was probably a highly pathogenic avian influenza that underwent a series of changes in several genes."

Moreover, there is emerging evidence in human infections with H5N1 that the hyperimmune response seen in 1918 cases may be occurring again. "Clearly there is cellular damage, and what we believe is happening with pathogenesis is that there is a cytokine storm’ — a massive inflammatory response," Uyeki said.

If H5N1 mutates in that ominous direction, the young and otherwise healthy may again form the rising middle of a "W" mortality curve. That’s the classic signature of the 1918 pandemic, as opposed to mortality in elderly and traditional risk groups as in the 1957 flu pandemic. Pandemic planners will have to be ready to adjust rapidly as the patient risk groups and clinical consequences become apparent.

"How are we going to use the limited amount of vaccine and antivirals that we have?" Pavia asked. "This is a very difficult ethical question. Is the overall goal to minimize hospitalizations and deaths or to keep society running efficiently? You can’t prioritize both adequately. So the decision was made [nationally] to prioritize mortality and morbidity as a target. Given this priority, there is a focus on people that are traditionally high risk. If we in fact have an outbreak that looks more like 1918, that approach may not be appropriate."

Either way, there are few comforting projections in any pandemic scenario. "If you look at the 1957 scenario just focusing on hospitalizations, we project about 865,000 hospitalizations — far in excess of our current surge capacity," Pavia said. "In a worst-case scenario of 1918-like [virus], we are looking at in the range of 10 million hospitalizations and 1.5 million ICU admissions."

On the other hand, for every worst-case scenario, there is a best one. The latter may be — at the very least — an indefinite continuation of the status quo, which finds the world preparing while H5N1 remains an inefficient transmitter between humans. Avian H5N1 is trying to crack the human immune system like a safe, but the combination is not lining up. For all the appropriate attention paid to the severe human infections and deaths, millions more have undergone similar exposures and remained asymptomatic. This bug is having a very hard time infecting people, let alone transmitting between them. By way of possible explanation, a recently published study found that cells in the upper portions of the human respiratory system lack the surface receptors that enable avian H5N1 virus to dock with the cell.

"Our findings provide a rational explanation for why H5N1 viruses rarely infect and spread from human to human, although they can replicate efficiently in the lungs," the authors reported.1

"They’re probably have been millions of people in very direct contact with [H5N1] infected, sick, or dead poultry," Uyeki said at SHEA. "We don’t have millions of H5N1 human cases. We don’t have hundreds of thousands of cases. We don’t have thousands of cases. We actually have relatively few H5N1 human cases."

Indeed, as of March 26, 2006, there were 186 confirmed human cases that have had resulted in 105 deaths in eight countries. "Generally, what you see in these cases [is that] they typically present late when they are quite ill," he said. "They present with fever and cough and shortness of breath, and some have had diarrhea. Typically, they have bilateral pneumonia, hypoxia, and many have severe respiratory distress and require mechanical ventilation."

Treatment options are relatively limited to antivirals, supportive care and antibiotics to stave off secondary bacterial infections. Yet this clinical picture is drawn only for the most severe cases — those heading for mortality more than half the time. Where are all the limited, mild infections with this pathogen? "We are only focused on surveillance for very severe respiratory disease, so we are not really accounting for mild or asymptomatic infection," Uyeki said. "But nevertheless, we’re not seeing many cases. At this time H5N1 illness in people remains a very rare disease."

The transmission puzzle

The transmission puzzle is that seemingly similar exposures result in infection in one person and non-infection in another. "The question is, why did this one [person] get it when everyone else in the village had the same exposures?" he said. "Why do you have three cases in one household, and yet — when you talk to everyone in the village — all the chickens are dead and everybody had the same exposure, if not more exposures. It starts to make you think that there could be genetic host factors that might predispose more susceptibility to infection and disease."

Most of the H5N1 human infections have occurred as sporadic cases in previously healthy people exposed to infected poultry. However, case clusters keep occurring, blinking on the epidemiological screen like an alarm that must be answered and investigated. Each time, the question is the same: Is this the beginning of efficient person-to-person transmission?

"We have seen clustering of cases in almost every country, where there are at least two cases in a household or among close contacts," Uyeki said. "Currently there has been no evidence of sustained human-to-human transmission. This virus does not have that ability at the moment, and therefore we do not have a pandemic. The clusters could mean different incubation periods. Someone gets sick one day, and then four or five days later another person in the household gets sick. That could suggest a variable incubation period after a common source exposure to sick or dead poultry or environmental exposures."

Though human transmission appears to be extremely rare, there are two published investigations that suggest H5N1 was transmitted to health care workers in 1997 and from a patient to family contacts in 2004.2,3 "One of the things about all influenza A virus — certainly avian influenza H5N1 — is that these are dynamic viruses," he said. "They continue to evolve. We are very concerned that the virus is changing to spread more easily to people. It hasn’t happened yet, but it is extremely important to investigate [all] clusters of cases."

The race is on

Even If the necessary viral mutation occurs and human-to-human transmission begins, pandemic influenza will not suddenly be everywhere at once. A pandemic would likely emerge in stages, giving hospitals a final, narrowing window to prepare.

"In pandemic Stage 3 or 4 — which is where we are now — it is time to get prepared and drill," Pavia said. "But Phase 6 — a true pandemic phase — will probably evolve in steps. There will be a phase where it is [beginning globally] but not yet in the United States. The steps that you take at that level may be a little bit different, [as you] command more resources to deploy and have the chance to move very quickly. When it reaches the United States, the next level of the plan has to be ready, and you need to be fully ready by the time it reaches your city."

While noting that substantial efforts have been made, Pavia lamented that federal pandemic planning funds recently came in at $7.1 billion less than requested. "[That] represents 2½ to three weeks for our current expenditures in Iraq," he said. "That is a huge problem."

Remaining gaps in the nation’s preparedness fall primarily in the areas of vaccine technology and production capacity; stockpiles of antivirals and hospital surge capacity. Research into novel flu vaccines continues apace, but preparedness is hampered by the low immunogenicity of prototype vaccines and the woeful state of domestic vaccine production capacity, he warned. For example, achieving human immunity against a pandemic strain may take two shots rather than one.

"The annual capacity of the current U.S. plants would be 14 million doses," Pavia said. "If we get about a threefold increase of immunogenicity from [vaccine boosting techniques] that will bring us to about 42 million doses. Clearly, we just don’t have the industrial capacity to produce a vaccine of such low immunogenicity with our current capacity."

Government enticements and liability waivers may reverse the longstanding vaccine production problems. In addition, $162 million recently was allocated for investment in surge capacity. That federal money is earmarked for purchase of some 6,000 ventilators, 50 million surgical masks, 50 million N95 respirators, face shields, gloves and gowns, he said. Impressive totals, but the numbers are tempered somewhat by the knowledge that many hospitals have long been operating with virtually no surge capacity at all. Coming up from dead empty, we may have to settle for a glass half-full.

"Let me just briefly state the problem, which is all too clear to everybody in this room," Pavia said. "We have little or no surge capacity in most of our facilities in the United States. We have not closed that gap terribly well. Our staff are very vulnerable to illness, fear, absenteeism, and overwork. Nosocomial transmission of seasonal flu has been well documented. This is a difficult virus to contain in part because virus can be shed up to 24 hours before symptoms. That will impact the spread within hospitals if asymptomatic staff and patients come in and spread [flu virus]."

As a pandemic looms, seasonal flu preparations should be leveraged toward a greater preparedness, he stressed. The growing push for universal public vaccination and the declining tolerance for nonimmunized health care workers are both being driven in part by the fear of a fateful H5N1 mutation. Similarly, research funding for influenza antiviral and vaccine development is at unprecedented levels. Still, the most confounding variable is time — or the lack thereof.

"We’re coming to this problem late," Pavia said.


  1. Ebina M, Yamada S, Ono M, et al. Avian flu: Influenza virus receptors in the human airway. Nature 2006. On the web at www.nature.com/nature/journal/v440/n7083/abs/440435a.html.
  2. Bridges CB, Katz JM, Wing HS, et al. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 2000; 181:344-348.
  3. Ungchusak K, Auewarakul P, Dowell SF, et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 2005; 352:333-340.