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H1N1 pandemic: IPs weather first wave, but warn against complacency as virus regroups
'If it be not now, yet it will come: The readiness is all.'
— William Shakespeare
On April 23, 2009, the oft-repeated pandemic influenza warning of "when, not if" became now. As reports came out of young, healthy people dying in Mexico City, the Centers for Disease Control and Prevention reported that a novel influenza A virus (H1N1) with genetic elements of swine, bird, and man was being transmitted between humans in the United States.
"I thought, 'Is this it?" says Sue Sebazco, RN, an infection preventionist and employee health professional at Arlington (TX) Memorial Hospital. "We've been told it's coming. You get this feeling of now we have to get into another mode — this may be it. If this is it, are we ready?"
Infection preventionists and hospital epidemiologists rolled out their pandemic plans to meet the threat of H1N1, and soon found themselves facing a host of complex issues like symptomatic health care workers, inundated outpatient clinics, delayed diagnostics, and eventual confusion about whether to stay at pandemic-level precautions or downgrade to seasonal flu measures. Sebazco immediately started reviewing available resources and chasing down reports that some health care workers were planning to visit Mexico or already had gone and returned.
"We didn't know what this was going to do, and we don't really know what's ahead of us yet," she says.
Though it continues to spread globally, there is growing evidence that the pandemic strain of swine influenza A (H1N1) lacks the level of virulence feared after the first wave of fatal cases in Mexico. Of course, at the onset of cases in the United States, IPs had to assume they might be dealing with a virus that could cause fatal infections and potentially overwhelm their supplies of critical medical equipment such as ventilators.
"Thank God, we got an opportunity to look at our planning in a real event that was not deadly," Sebazco says. "But that first weekend we worked closely with our medical society ethics consortium on the whole issue of triaging ventilator use and things like that. That's one plan that nobody wants to go to, but we did provide counts of beds and ventilators everyday to our emergency preparedness center."
The Mexican mystery
Overall, it appears hospitals and the health care system rose to the occasion, but the caveat remains that had H1N1 been a less forgiving virus in the United States, we might be describing a much different outbreak, marked by serious infections in health care workers and many more fatalities among patients. A veteran health care epidemiologist who consulted with Mexico City health officials and did hospital rounds there in early May described a dramatically different picture south of the border.
"I saw a large number of people in their 20s, 30s, and 40s very ill, intubated in critical care," recalls Richard Wenzel, MD, of Virginia Commonwealth University in Richmond. "At the very least, one has to conclude this virus can kill. It would be foolish for the United States to get complacent and think that it is a mild respiratory infection. I was very impressed with the severity of illness in very young people."
Indeed, initial reports of relatively young people dying in Mexico invoked the infamous 1918 pandemic, which — although a completely different virus — also was an H1N1 strain. Though the first cases in the United States have been milder infections, the threat remains that a "cytokine storm" may gather in the immune systems of those ironically healthy enough to have a hyperreaction.
"But [the Mexican patients] are not coming in with community-acquired pneumonias like in 1918-1919," Wenzel tells Hospital Infection Control & Prevention. "The severe cases at least are more like H5N1 (avian flu). They are coming in with low blood pressure, marked leucopenia, and their muscle enzymes are elevated pretty high."
Flu has been known to attach to muscle cells and, in some cases, this led to renal failure, he said. "They are very hypoxic, and at the height of the epidemic, about a third of the people admitted were being put on respirators," he says.
One of the emerging theories about the severity of cases in Mexico is that they represent only a fraction of total cases, many of which went unreported because they were mild or asymptomatic. "I think the denominator is going to turn out to be much, much bigger than what is being reported," Wenzel says. "In my view, there are probably at least 50,000 cases if not more. The numerator of severity as measured by mortality will probably go down."
Concurring with this theory was influenza pandemic expert Eric Toner, MD, senior associate with the Center for Biosecurity at the University of Pittsburgh Medical Center.
"I suspect it is a surveillance artifact," he says. "We know that people from this country traveled to all different parts of Mexico and became infected. They did not have known contact with people that were sick, which says to me there must have been a considerable amount of community spread throughout Mexico. The denominator of the case fatality ratio must be very large. There are lots and lots of people that did not have serious infections."
The possibility that underlying genetic factors make the Mexican population more vulnerable to the virus also is under discussion, as ongoing genomic research indicates such disease variations in other areas.1 Another factor Wenzel noted on his clinical rounds in Mexico was that very few serious cases had a history of seasonal flu immunization, suggesting there might be some "cross-reacting antibodies" even though the virus is completely different from any prior flu strain. "It's too early to say, but in the very severe cases, almost no one had prior vaccination," he added.
In that regard, the CDC and the Food and Drug Administration have taken the initial steps to begin seeding and producing an H1N1 vaccine with an eye toward fall flu season in the Northern Hemisphere. The flu season is just getting under way in the Southern Hemisphere, and epidemiologists are anxious to see if a virus that appears highly transmissible manifests more widespread virulence. While agreeing that it is prudent to prepare now, a leading vaccine expert openly questioned mass producing a vaccine against the strain that is currently circulating.
"Technically it's a pandemic, because it involves several countries, clearly can be fatal, and is easily spread from person to person," says Paul Offit, MD, infectious disease chief at the Children's Hospital of Philadelphia. "But it's not how one thinks of a pandemic — a worldwide epidemic associated with a high degree of fatality. I don't think there's ever been a pandemic that caused less than a million deaths. That certainly doesn't appear to be [what we will see] with this strain. If you were going to characterize it, you would call it a mild epidemic, unless we are going to call every flu season a public health emergency."
Indeed, amid all the mass media coverage and daily case counts the CDC reminded repeatedly that some 36,000 people fall to seasonal flu every year in the United States. In that context, H1N1 has shown a striking lack of virulence in cases outside of Mexico, as only a handful of deaths were occurring even as the virus spread globally.
A former member of the CDC's Advisory Committee on Immunization Practices, Offit noted that the strains for seasonal flu are already earmarked for production, so an H1N1 virus would likely have to be a separate vaccine. Moreover, matching a vaccine to this strain could be of questionable benefit if the virus mutates further and becomes more virulent.
"I agree let's get ready, but if this is all it is — a flu strain that causes a very mild illness, do you need to [mass produce] a vaccine for this?" he says. "The only way you could argue this is to say it may mutate over time and become much more virulent. But it that's true, that [strain] becomes the vaccine — not this strain."
Novel strains of flu that in the past would have gone undetected are more likely to be recognized now with ramped-up global surveillance and testing due to the emergence of pandemic candidate avian influenza A (H5N1). "Just because a strain is new — has pandemic potential — that doesn't mean it is going to be a pandemic," he said. "The interesting question is, 'How often does this happen?' I think the answer is honestly, 'We don't know.'"
Though the severity of illness in Mexico remains under investigation, there also is evidence that this H1N1 strain lacks a key virulence marker in its genetic makeup. Missing is the protein PB1-F2, a "molecular signature" for virulence that has been found in the 1918 virus and in the highly lethal H5N1 virus, says Peter Palese, PhD, chairman of the department of microbiology at the Mount Sinai School of Medicine in New York City.
"All available sequences of different swine viruses show that these viruses lack [that] protein," he says. "One cannot exclude the possibility, that swine viruses may acquire this virulence gene in the future. Most regular H1N1 viruses, which have been circulating for years, also do not express a PB1-F2 protein, and they have not acquired this virulence gene over time. Thus, it is very possible that the swine H1N1 viruses will not do it either."
Two billion might be infected
Still, the World Health Organization predicted some 2 billion people might eventually be infected with the virus, suggesting many more deaths will occur as the disease reaches immunocompromised populations.
"Most of us that spend our work day thinking about pandemic flu, think that this probably is the beginning of a pandemic," says Toner. "It will likely return in the fall and [result in] a significant flu season with a novel virus. This gives us a window of opportunity over the remaining spring and summer to get prepared."
The mouse that roared
Though he doubts the virus will become more virulent, Toner emphasized it could do sufficient damage in its present form. "We can expect an awful lot of people in the fall to have flu and it may be a pretty bad flu season just because of the number of infections," he says. "[Vaccine production] will be largely driven by what happens in the Southern Hemisphere. If we see lots of cases of this novel H1N1 in South America and Australia, then clearly we will be making vaccine for the Northern Hemisphere."
Yet as this issue went to press, the erstwhile "swine" flu — a moniker dropped because of misinformed pig culling and avoidance of pork consumption– was starting to be viewed more like the mouse that roared. Even with the WHO threat level ratcheted up to 5 out of 6 — indicating continuing international transmission of a novel flu virus and a "strong signal that a pandemic is imminent" — the CDC had to take the extraordinary step of discouraging "swine flu parties."
These are gatherings during which people feel safe enough to have close contact with a person who has novel H1N1 flu in order to become infected with the virus. "The intent of these parties is to become infected with what for many people has been a mild disease, in the hope of having natural immunity to the novel H1N1 flu virus that might circulate later and cause more severe disease," the CDC stated. "While the disease seen in the current novel H1N1 flu outbreak has been mild for many people, it has been severe and even fatal for others. There is no way to predict with certainty what the outcome will be for an individual or, equally important, for others to whom the intentionally infected person may spread the virus."
Presumably, no such warning was needed in Mexico.