West Nile Virus and Other Hot Topics
"Our perennial topic this morning is West Nile virus (WNV)," began Rocky Bigbie, DVM, MS, director of field veterinary services with Fort Dodge Animal Health, at the 2005 Western Veterinary Conference held Feb. 20-24 in Las Vegas, Nev. He also focused on myriad hot topics in equine veterinary medicine, discussing WNV vaccination guidelines, influenza vaccination challenge, vaccine care and handling, drug compounding, and the veterinarian's role in detecting and fighting bioterrorism.
He began by reviewing some of the basics of WNV infection in horses, its life cycle and transmission, and its dynamics in herds. Almost all of the virus resides in the bird population; mosquitos become infected by feeding on infected birds, then they pass it on to horses and humans when they feed on them afterward, he said.
He showed a video of an affected, ataxic (incoordinated) horse to illustrate the severity of neurological compromise. The horse was shown in a field, where he kept floundering around in circles and falling with greater incoordination of the hindlimbs than the forelimbs. "This horse lived; he never lost the ability to get up, and that is often the discriminator between loss and survivability," he reported. Mules and donkeys are just as susceptible to WNV as horses, he noted, adding that all horses are susceptible but older ones are more likely to die.
"Mortality may result from injuries incurred during acute disease, such as severe lacerations, head trauma, fractures, sepsis, or from an owner's thin wallet (if an owner is unable or unwilling to provide the care these horses need to recover)," he added.
However, vaccination can prevent or mitigate clinical signs of the disease in horses, he noted. "But like all herd health endeavors, if you just vaccinate and ignore all the other measures you can take (to minimize mosquito activity around your horses), any vaccination is doomed to fail in the face of high levels of exposure," he warned. "Researchers have harvested 10,000 mosquito larvae from one tire (empty tires can collect water and become the perfect mosquito breeding grounds).
"Also, you hear some people talk about herd immunity (the theory that by vaccinating some members of a herd, you will decrease any viral shedding and thus minimize the challenge to all animals)," he went on. "But in a herd of horses, if you had 100 and you vaccinated 99 (against WNV), that 100th horse is just as susceptible as he was with no vaccination of his herdmates. The disease isn't transmissible from horse to horse, so you don't reduce shedding with vaccination. Each horse stands alone when it comes to this disease."
So how often might a horse be exposed to the virus? He reported that in one study presented at the 2003 American College of Veterinary Internal Medicine conference, 317 horses had blood sampled on premises with at least one clinical case of equine WNV in peak WNV season; the samples were analyzed for recent WNV exposure with an IgM capture ELISA test (to measure levels of IgM, one type of antibody). Overall, 24.6% seroconverted (showed an IgM response indicative of WNV infection); this included vaccinated and unvaccinated horses. "Many of those horses may have had such a mild case that no one noticed," he said, "but they were definitely exposed."
Treatment of affected horses includes supportive care, padded stalls, deep bedding, head protection, and hydration, he said, adding that antiviral drugs could be effective but were expensive.
WNV Progression and Risk
Turning briefly away from horses but not away from the barn, Bigbie reported that cats and dogs are easily infected with WNV, but don't get sick. He added that 30 dogs reportedly showed clinical signs of the disease in 2003, but they all had some form of predisposing immune decrement.
In 2004, he said, there were 1,305 cases of equine WNV in 37 states with the vast majority in California (534 vs. only two in Georgia and five in Florida). "There was a 43% mortality rate (for affected horses) in California--much higher than other areas," he stated. "One theory is that most of the people who were going to vaccinate horses had already done so in the past two years, so most of the affected horses might belong to people who weren't going to vaccinate anyway and were less willing to treat the horses aggressively, not that the virus is getting any bigger, meaner, faster, or stronger.
"One problem is that many people think WNV just went away," he lamented. "There's been a war, an election, and a lot of other things to talk about rather than WNV. Since there's no longer the WNV alert every night on the news, most people think the disease just went away, but it was actually worse in 2004 for humans than in previous years. And the risk in people, birds, and horses mirror each other."
He went on to report that in early February, bird and human cases had been confirmed one to two months earlier (respectively) than last year, and the peak season is still in August/September regardless of where you are. "Is the second year always the worst, as some say?" he asked the audience. "In 2003 there were only three (equine) cases, so some consider 2004 California's first year. The West Coast may be in for an even worse (equine WNV) year in 2005."
He predicted that epidemiologically, WNV will start behaving like Eastern and Western equine encephalitis (EEE and WEE), which both affect only about a half dozen cases per year. "Georgia, Florida, and the southern states usually have about five to 10 cases in unvaccinated animals," he said. "But last year, many owners didn't vaccinate (horses) for EEE. Maybe they thought there was cross protection (from the WNV vaccine), or maybe they just chose not to vaccinate for EEE that year. So Florida went from 5-10 to over 200 cases. If we don't vaccinate for WNV, we will see the same spike in cases. It is endemic and not going away."
Safety and Efficacy
"Beware of the Internet!" he warned attendees. "Many people suddenly question you because a total stranger on the Internet has told them that something you're doing is not right. For example, there was the fuss about the safety of West Nile Innovator (Fort Dodge's killed WNV vaccine) in pregnant mares. We fought with this, and it didn't matter what kind of scientific evidence there was, some people thought it was causing abortions and deformed foals. Whenever something goes wrong, the most conspicuous thing in the horse's history must be to blame, so rare abortions and deformed foals were blamed on West Nile Innovator."
However, he reported that a recent article published in the Journal of the American Veterinary Medical Association (JAVMA) evaluated the administration of Fort Dodge's WNV vaccine to pregnant broodmares concluded that: "Vaccination of pregnant mares during any stage of gestation was not associated with increased pregnancy loss.
"For some science and emotion don't mix, but maybe this study will help with some of your clients who have reservations about the vaccine," he commented.
Bigbie briefly discussed the WNV vaccination guidelines recently released by the American Association of Equine Practitioners. "A 'strategic' booster tries to lay that booster on period of highest risk," he explained. "So if you're using one (booster) dose, lay that peak immunity on in late summer/early fall, not late spring/early summer (for both vaccines on the market)."
Foals are recommended to be vaccinated starting at three months of age at four- to six-week intervals with a three-dose initial series, with a fourth dose at one year, he said. "Vaccinate clinically affected horses one year after recovery," he added.
He spent a little time discussing another recently published study in the American Journal of Veterinary Research in which naïve horses were challenged with WNV 26 days after a single dose of Merial's Recombitek WNV vaccine (which like Innovator is labeled for a two-dose initial series). The conclusion of the study was that the vaccine offered early protection even in the absence of measurable antibody titers (three of nine horses had no antibodies via plaque reduction neutralization test, so the immunity must be cell-mediated immunity, concluded the report).
"I think some practitioners might have misinterpreted this result to mean one-dose immunity, but this was just a 26-day challenge," cautioned Bigbie. "Both dose labels are based on a one-year challenge, and we don't know how long a one-dose initial series will protect the horse. Also, consider the conditions in which rapid onset is required, such as foals? This study was done in adults, so it may not be germane to foals with maternal antibodies against WNV."
He also explained that protection despite no antibody response is routinely seen in challenge studies.
An equine influenza challenge study presented at the 2003 AAEP convention found comparable immune responses to several different commercially available vaccines, Bigbie reported. Following a very severe challenge, Boehringer-Ingelheim's Calvenza worked a little better against this challenge (KY 99 strain), but all vaccinated groups had a highly significant immune response.
However, he noted that the Fort Dodge vaccine used in this study was Fluvac Plus, not the Fluvac Innovator that has been on the market for a few years now. He also stated that the strain of virus used in Fluvac Innovator (which is different from Fluvac Plus's strain) is the closest strain (KY 97) evolutionarily to flu strains currently making horses sick in the U.S. of the various currently marketed equine influenza vaccines.
Vaccine Care and Handling
"You don't have to be a stooge to mess this up--a lot of very smart people are not aware of how to properly handle vaccines," Bigbie said. Most people that work at a clinic don't know that temperature is important and that they need to maintain records of serial numbers, etc., he noted. Regarding temperature, he said that refrigerators used to store vaccine are usually too cold rather than too warm.
"It can't sit in storeroom and get up to 90 degrees, or sit on a back porch and freeze," he warned. "Do not use compromised vaccine. Vaccine that has turned yellow does not mean use it faster, it means STOP!
"What's in a vaccine?" he asked. "Antigen (which stimulates the targeted immune response), adjuvant (which boosts that response), preservatives, the carrier, and a buffer system/pH indicator. Why are adjuvants in vaccines? They bolster the immune system and are very important to high immunogenicity.
"But they're also very sensitive to temperature," he went on. "You want it closer to 45 degrees than 35. Room temperature is OK, as the vaccine stays still cool enough with short times at room temperature."
But even a brief moment of freezing damages the vaccine by separating the antigen-adjuvant complex. "Do not freeze the vaccine!" he warned. "It's documented with research. One veterinarian I worked with gave 20 doses in one day, and had 18 horses come up with big reaction knots (after having used the vaccine successfully many times before and since). We couldn't figure out why for awhile, but it turns out that it froze, and the practice manager knew but the vet didn't. Keep a thermometer in there and make sure you're not freezing it. If you happen to look at vaccine that's barely frozen, you might see little crystals floating in there, but just holding it in your hand will melt them and then it doesn't look any different.
"And shake it well before use--it is a suspension, not a solution," he added. "Sediment in the bottom happens when it sets for a long time. In a 10-dose tank, you could draw up all the adjuvant in one syringe and give it to one horse (if it had settled out)." This would be bad because other horses would get very little adjuvant and he'd get very little antigen. If a syringe sits out and settles, he said to draw up an air bubble and tip it back and forth to remix the suspension.
Another concern with vaccine quality is contamination. Bigbie stated that the Innovator vaccine includes a phenol red indicator that changes the vaccine's color to yellow or red as pH increases from 6.8-8.2. "This indicates contamination because the pH has changed because of something growing in that vial," he explained. "Don't use vaccine that has changed color."
During a question and answer session after the presentation, an attendee asked what causes the bump some horses occasionally get at a vaccination site. "There is always a granuloma (inflammatory lesion) at the site of vaccination," he answered. "Most of the time, it's too small even to palpate. Hopefully, a visible knot will shrink down with time. Some horses, for whatever reason, just have a more prominent response to something in there--antigen, adjuvant, whatever. Another possibility is a plaque that is related to vaccination, urticaria (transient allergic skin reaction), etc."
"Some practitioners are using things that maybe weren't what they thought," began Bigbie on the subject of medications that are improperly or illegally compounded (made by a pharmacy from bulk ingredients). "The FDA has put a bit of a crunch on people who are drug pirates--not even compounders--mimicking approved animal drugs."
He cited one example of compounded omeprazole (which is illegal since there is an FDA-approved omeprazole product, GastroGard); this product's label said it contained omeprazole with bismuth salicylate. "That (bismuth salicylate) will tie up the omeprazole and make it worthless!" he stated. "And do you think they did studies to evaluate that product's stability?" He added that one study of 10 compounded omeprazole products found that they contained only 6-74% of the amount noted on the label.
He also described a study from the University of California, Davis, which "clearly showed that these (compounded omeprazole) products don’t work," he said. "Anyone using them is either unethical or unaware. I want to make you aware."
Compounded ivermectin (which is also illegal) is another hot topic; Bigbie briefly discussed a study published in the Journal of the American Veterinary Medical Association on ascarid resistance, asking the audience if perhaps resistance was being facilitated by owners using compounded ivermectin products with only one-third the amount of ivermectin they should have? "This is exactly how you create resistance," he warned.
He also noted that studies have tested other illegally compounded products. These found that compounded ketoprofen contained anywhere from 50-100% of the labeled amount, and compounded amikacin concentration ranged from very low to 150%. "You could kill a dehydrated foal with too much amikacin," he cautioned.
Other notes about compounded products included that compounded boldenone had been found to contain 5% unknown contaminants, and that some compounders put implausible expiration dates on their labels (implying far longer shelf lives for products than pharmaceutical companies have been able to verify).
"Would you use illegally compounded drugs on your own animals?" he asked the audience.
Bigbie's last topic of discussion was the veterinarian's role in detecting and counteracting bioterrorism, which he defined as the use of microorganisms or toxin to cause disease
"A 2002 JAVMA article said that state veterinarians are significantly less likely to have knowledge of bioterrorism incidents within their state or district than state public health officers," he reported. But bioterrorism that affects animals could have just as big an impact on a country; he added that one estimate of what might happen if foot and mouth disease hit the United States was that the cost of putting beef on the dinner table would increase sharply overnight.
"Veterinarians need to be vigilant," he said. "Think horses, but don’t completely forget the zebras. Know what diseases to report, know the reporting chain, and know who to turn to for help." (The American Veterinary Medical Association can provide this information.)
He explained that a terrorist-introduced disease might be seen in animals first (veterinarians might be the first line of defense). Veterinarians should be alerted to possible bioterrorism if a disease showed clustering of morbidity or mortality in a population, unusual age distribution of affected animals, animals affected that are normally healthy, or if the disease is unusual for that area, he said.
About the Author
Christy West has a BS in Equine Science from the University of Kentucky, and an MS in Agricultural Journalism from the University of Wisconsin-Madison.
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