DVMs who handle birds at increased risk of avian flu, study finds

IOWA CITY, IOWA — Veterinarians who regularly work with birds have substantially higher levels of antibodies in their blood against avian virus strains than do control subjects, according to a two-year study conducted by researchers at the University of Iowa College of Public Health.

That's a clear signal that those DVMs would be at high risk for infection in the event of a serious avian flu outbreak and argues that they should be given the same priority access to pandemic influenza vaccines and antivirals that public-health doctors and nurses would have, the recently published study says.

Kendall P. Myers

The researchers, led by Kendall Myers, a doctoral student in occupational and environmental health, and Gregory Gray, MD, UI professor of epidemiology and director of IU's Center for Emerging Infectious Diseases, performed a controlled, cross-sectional seroprevalence study among 42 Iowa veterinarians and 66 healthy control subjects using serum samples collected from 2004 through 2006.

The study showed that, compared with the control subjects, DVMs who regularly worked with birds had greatly elevated titers against the H5, H6 and H7 avian influenza virus strains, indicating previous infections with those strains, likely due to mild forms of virus that occasionally circulated among wild and domestic birds.

"Veterinarians and others with frequent and close contact to infected birds may be among the first to be infected with a pandemic strain of influenza," Myers says. "They have the potential to spread the illness to their families and communities. Because of this, we suggest that veterinarians should be considered for inclusion on priority access lists for pandemic influenza vaccines and antivirals."

Of the 42 veterinarians in the study, 32 worked with live chickens, 21 with ducks, 18 with turkeys, 12 with geese and seven with quail.

Few DVMs in the study reported that they regularly use protective gloves and masks.

However, that simple measure could help reduce virus transmission, Myers tells DVM Newsmagazine.

Receiving an annual human-influenza vaccination also might be a mitigating factor, she adds.

Gray explains that, "While these earlier avian-flu infections (antibodies for which showed up in the blood of veterinarians) were likely mild or subclinical, the story might be very different should aggressive strains enter the United States like the H5N1 strains infecting domestic birds in Asia.

"It is increasingly important to identify the best ways to protect veterinarians and other agricultural workers most at risk for zoonotic diseases," Gray believes.

How well prepared is the United States for a pandemic outbreak of H5N1?

"We're more prepared than we were six months ago, and not as well prepared as we will be six months from now," Gray says. "But there's no question we aren't yet ready to handle anything with a fast rate of transmission."

The American agriculture industry "has been particularly neglected in pandemic planning," Grau adds. Should the virus infect swine and poultry, as occurred with the pandemic strain of flu that killed millions in 1918, "it would greatly increase the speed of transmission to humans," he says.

Gregory C. Gray, MD

DVM Newsmagazine asked Myers to elaborate on several key points from the study. Here are our questions and her responses:

DVM: Is there a surprise element to your finding that DVMs who work with birds would be at increased risk in the event of a major outbreak? Wouldn't that be a logical assumption?

MYERS: We suspected that veterinarians would be at greater risk for avian influenza infections. In this pilot study, we sought to estimate the seroprevalence of antibodies against avian influenza viruses in veterinarians with exposure to birds and to determine risk factors for infection.

We examined a number of possible risk factors, including age, chronic medical conditions, race and ethnicity, medication use, military service, children in the home, and smoking.

Potential occupational risk factors included working with birds known to be infected with influenza, number of years of exposure to birds and the use of protective personal equipment, such as gloves and masks.

Veterinarians who reported having examined birds known to be infected with influenza presented an increasing trend of being seropositive, compared with veterinarians without this exposure and with control subjects.

No other risk factors showed a statistically significant association with elevated antibody titers.

DVM: How many veterinarians participated in the study, and where and how did you select them?

MYERS: We enrolled a total of 75 veterinarians who were attending a conference of the Iowa Veterinary Medical Association in the spring of 2004. For this study, we included only veterinarians who reported having exposure to birds, resulting in 42 veterinarians. Most of them were from Iowa. Control subjects were volunteers associated with the University of Iowa (Iowa City) who were enrolled in the study during the spring of 2006.

DVM: Did the study look at any other risks besides avian influenza?

MYERS: We also performed a seroprevalence study of swine influenza viruses. From the same group of veterinarians described above, a total of 65 reported exposure to pigs. We found that these veterinarians also had increased odds of being seropositive for the swine H1N1 and H1N2 viruses. This was published as a separate study and is available at www.pubmedcentral.nih.gov/.

DVM: What is the significance of the higher levels of antibodies in the blood of DVMs against the milder H5, H6 and H7 strains, indicating previous infections? Might that result in some immunity to H5N1?

MYERS: There are many different strains of each influenza subtype, but we tested for antibodies to only one strain of each of H4 through H12 subtypes.

Avian influenza can be categorized as either highly pathogenic avian influenza (HPAI) or low pathogenic avian influenza (LPAI). All strains tested were low pathogenic avian influenza (LPAI). To our knowledge, only H5 and H7 subtypes are capable of becoming HPAI.

Based on laboratory data, there is some cross-reactivity between strains, so having antibodies to a different H5 strain may theoretically confer some partial immunity to H5N1.

On the other hand, there may be enough difference between the HPAI H5N1 strain and an LPAI strain that any partial immunity is useless. Generally, antibody titers of at least 1:40 are necessary to provide protection, and most of the veterinarians had titers lower than this. So, while the titers were high enough to indicate previous infection, they aren't considered high enough to provide immunity.

The study is unique in that we found evidence of infection with these viruses when surveillance had not detected LPAI in Iowa in many years. Distribution of hemagglutinin subtypes in birds varies geographically, temporally, and by species. However, the H6 subtype appears to be commonly found in birds, whereas H5 and H7 are less common.

Why these veterinarians have elevated risk for antibodies to subtypes not frequently found in birds is unknown. Different subtypes are likely to vary in their ability to infect and produce an antibody response in humans. In addition, surveillance data for avian species are limited, and it is possible that outbreaks of these subtypes have occurred but have gone unnoticed.

DVM: Please elaborate on the statement in your paper, "Birds are the source of all influenza viruses in all other species." What are the implications of that?

MYERS: Phylogenetic studies have shown that aquatic birds are the original source of all influenza viruses. Waterfowl are the natural reservoir for all 16 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes, which occur in many different combinations (H5N1, H7N7, etc.).

Influenza viruses in waterfowl are genetically stable; they don't change much over time. However, when the viruses infect domestic birds like turkeys, chickens and domestic ducks, they undergo rapid genetic changes. In wild waterfowl, influenza typically doesn't cause any symptoms at all. When transmitted to poultry, influenza virus may undergo mutations and cause illness, sometimes severe. These viruses can be transmitted from poultry to humans, but typically LPAI doesn't cause clinical symptoms in people and isn't spread from person to person.

There are two separate issues that concern us regarding avian influenza. 1) Direct infection causing severe illness, such as is occurring with H5N1, and 2) the potential for genetic changes in the avian virus that give it the ability to become easily transmitted from human to human.

When an animal or human is simultaneously infected with different strains of influenza, the two viruses can exchange genetic information. This is called reassortment, and it results in a novel progeny virus to which humans are immunologically naïve. If the resulting virus acquires the ability to be easily transmitted between humans, a pandemic may result.

Essentially, an avian influenza virus is one that is adapted to birds, and a human influenza virus is one that is adapted to humans. The technical distinction between an avian virus and a human virus is genetic, with an estimated 52 genetic changes distinguishing avian influenza strains from those that spread easily among people. A critical difference between avian and human influenza is that avian influenza viruses bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. The alpha 2-3 links are found in the intestinal tract of birds, while the human respiratory tract has predominantly alpha 2-6 linkages.

This receptor specificity is a key factor in host-range restriction. If an avian virus acquires the ability to bind to human receptors, it is likely to become adapted to humans and transform into a human virus.

Currently, only H1N1 and H3N2 viruses are circulating widely among humans. Although they originated from avian strains when they first emerged in the human population, they now are considered human strains. H1N1 emerged suddenly and explosively in 1918 and circulated until 1957, when it was replaced by an H2N2 virus. H2N2 circulated until 1968, when H3N2 emerged and H2N2 disappeared. H1N1 re-emerged in 1977, possibly by escaping from a laboratory, although its origin is uncertain. In each case, the newly emergent virus had avian origins. The viruses quickly mutated and became adapted to humans, so they were no longer considered avian viruses. Each time the Hemagglutinin subtype changed, a pandemic occurred.

DVM: Is an H5N1 outbreak in the United States inevitable? How much vaccine would be available?

MYERS: Many do feel that the spread of H5N1 into birds in this country is inevitable. The geographic range of the virus is rapidly expanding and efforts to contain the virus have been unsuccessful.

The larger question is whether a human pandemic is inevitable. The consensus among the public-health community is that another influenza pandemic is inevitable. Pandemics occur, on average, about every 30 years, and it has been 39 years since the last one.

As mentioned earlier, a pandemic occurs when a new subtype enters the human population. The viruses causing the last three pandemics originated in avian species. Many believe that it is just a matter of time before H5N1 adapts to humans and causes the next pandemic. Others suggest that if H5N1 were going to cause a pandemic, it would have happened already, and that the virus may never acquire the ability to transmit efficiently among humans. It is impossible to predict how H5N1 will evolve or which strain will cause the next pandemic.

The first human vaccine against H5N1 was approved by the FDA in April 2007. A limited amount of it is being stockpiled and will be considered for early use in the event of an H5N1 pandemic. About 13 million doses, enough for 6.5 million people, have been ordered by the federal government. The HHS pandemic plan lists priority groups for vaccine distribution. Agricultural workers and others with exposure to birds are not included in priority lists.

DVM: Were there other findings in the study of particular interest to veterinarians?

MYERS: Few veterinarians in this study reported using personal protective equipment such as gloves and masks. A study done by the Center for Emerging Infectious Diseases at the University of Iowa demonstrated that use of gloves during swine-confinement work noticeably decreases the risk for swine influenza virus infection. Thus, a simple personal protective measure might do much to reduce zoonotic virus transmission.

Receiving the annual human influenza vaccination would not only protect veterinarians from the seasonal flu; it may also minimize opportunities for reassortment between avian and human influenza viruses, decreasing the likelihood of generation of a pandemic influenza strain.

The Occupational Safety and Health Administration (OSHA) published a guidance document for protecting employees against the avian flu that veterinarians and other animal workers might find useful. It may be accessed at www.osha.gov/dsg/guidance/avian-flu.html

The UI study is published in the July 1 issue of Clinical Infectious Diseases, available online at www.journals.uchicago.edu/CID/home.html.