Lower airway disease is all too common among the horse population--the occasional cough in the young racehorse that belies serious disease, the wheezy horse which can't tolerate his barn, the backyard horse which always seems to have a cough or nasal discharge. It's no surprise that researchers around the world are engaged in finding the causes and cures of inflamed airway passages. Efforts are primarily directed toward inflammatory airway disease (IAD) and heaves (also called chronic obstructive pulmonary disease, COPD; or recurrent airway obstruction, RAO).

For the latest in what's going on to help your horses breathe easier, read on.

Biologic Basics

The secret's in the secretion. At Michigan State University (MSU), a team of researchers is investigating the relationship between heaves and excess mucus secretion, the accumulation of which contributes to airway obstruction.

Heaves is the result of airway inflammation that is induced by inhalation of organic dust--usually stable dust. This inflammation leads to airway obstruction that is, in part, due to accumulations of mucus in the airways. When heaves-affected horses are kept on pasture, their airway inflammation wanes, but accumulations of mucus persist. To understand what's happening, researchers have developed probes to look at the genes that are responsible for producing mucus in horse airways, says Ed Robinson, BVetMed, PhD, Matilda Wilson professor in large animal clinical sciences at MSU.

"We know now that one of these genes is turned on when the horses have inflammation," he says. "What we're going to do next is to see if it stays turned on when horses are out in pasture or if it gets turned off.

"The other thing that happens when horses get inflammation is that the mucous cells in their lungs live for a longer period of time," Robinson continues. "When cells are living longer and the horse keeps producing new ones, they end up with more cells producing mucus in the lungs."

By determining why these changes occur, researchers might be able to interfere with these processes through drug therapy or by genetically selecting away from the disease. "Our long-term goal is to identify foals or yearlings that might develop heaves later in their life," Robinson says. "Such a gene test would allow owners to be very careful not to expose a heaves-prone horse to very much hay dust or to stable a clear horse in a conventional fashion."

When good signals go bad. Virginia Buechner-Maxwell, DVM, MS, Dipl. ACVIM, associate professor of large animal internal medicine at the Virginia-Maryland Regional College of Veterinary Medicine, is searching for the errant signal(s) in the immune system that causes the immune system to overreact when exposed to inhaled debris such as mold or hay dust. "In normal animals (and people), the immune system does not react to moderate amounts of mold and hay dust in the environment," she says. "But in horses with recurrent airway obstruction, a signal is turned on that tells the body to gear up and fight," causing clinical signs such as difficult breathing and coughing.

Lymphocytes, a type of immune cell, might play a role in directing this response. In normal horses, this response is prevented because the lymphocytes get a signal to die, rather than react, when they encounter mold or hay dust particles. In RAO horses, the lymphocytes do not die when they should, and there might be a relationship between the two events.

Buechner-Maxwell is hoping to better understand that relationship by collecting and analyzing cells from the airways and blood of affected animals. "Understanding the mechanism--why these cells remain active--might lead to either identifying animals early on that have this problem, so as to apply avoidance mechanisms, or to developing a very specific therapy to stimulate death of those particular cells."

In a related study, Buechner-Maxwell is investigating how corticosteroids are able to turn off these signals in RAO-affected horses. "Although corticosteroids are very effective at turning off the immune response in the lungs, the downside is they work in a very general way and turn off the whole body's immune response," she explains. This leaves a horse vulnerable to infection. By identifying the specific signals that trigger an inappropriate immune response in the lungs, researchers could develop a very targeted therapy to block these events, without significantly affecting immune function in the rest of the body.

More signal searching. Similarly, Jean-Pierre Lavoie, DMV, Dipl. ACVIM, professor of equine medicine on the Faculty of Veterinary Medicine at the Université de Montréal, and McGill University researchers James Martin, MD, director at Meakins-Christie Laboratories' Department of
Medicine, and Qutayba Hamid, MD, PhD, associate director at Meakins-Christie Laboratories' Department of Medicine, are looking for the cause of signals that trigger a hypersensitive pulmonary cell response linked with the development of respiratory signs and airway inflammation.

"By understanding the cascade of molecular signals that result in airway inflammation and obstruction in heaves, new therapy targeting specific mediators could eventually help control this condition in horses," Lavoie states. "These studies could result in a new and rapid diagnostic test for the disease that could help identify susceptible animals at a young age."

When and why. At the University of Guelph, Laurent Viel, DVM, PhD, professor of large animal internal medicine, is striving to find what predisposes young horses to heaves and how early the condition starts. "Does it start when, as babies, they get some sort of infectious respiratory condition that later predisposes them to become allergic to dust or mold? Is it a progressive allergic condition?" If so, handlers could more carefully monitor the respiratory health of at-risk youngsters and, if warranted, provide frequent treatment with inhalers to maintain optimum health and performance levels.

Stabling

Dust and the heavey horse. It's known that heaves-affected horses develop clinical signs of the disease within hours of being stabled in a dusty environment. Recently, Professor Bruce McGorum, BVM&S, of the Division of Veterinary Clinical Studies, and Scott Pirie, BVM&S, MRCVS, of the University of Edinburgh, completed several studies involving a specific component of dust.

In one trial, researchers quantified the levels of endotoxin (a component of bacteria) in three types of horse environments: 1) a conventional stable that contained hay and straw, 2) a low-dust environment containing wood shavings and haylage, and 3) at pasture.

McGorum explains, "Horses wore personal dust samplers quantifying the amount of dust immediately adjacent to the nostrils, giving an indication on how much dust and endotoxin the horses were breathing in." Horses in the hay and straw stables inhaled significant concentrations of dust containing high levels of endotoxin. Indeed, the levels of endotoxin to which the horses were exposed exceeded levels that are known to cause respiratory disease in humans. The dust and endotoxin levels in the wood shavings and haylage environment were lower, while levels at pasture were negligible.

"It was clearly shown that endotoxin levels were very dependent on the environment," McGorum states. "All we need to do to prevent heaves is to keep our horses in low-dust environments."

The study also confirmed that the endotoxin component encountered in dusty environments is a significant contributor to heaves. For example, the removal of endotoxin from stable dust was shown to result in a marked reduction in the severity of heaves in susceptible horses.

Finally, in collaboration with researchers in Australia, McGorum and Pirie studied the relationship of endotoxin and IAD. "With this condition, in contrast to heaves, horses don't develop overt airway obstruction or increased effort in breathing, but do have increased quantities of mucus and inflammatory cells in the airways, chronic coughing, and reduced exercise tolerance. This condition is a common problem in young racehorses, especially those horses coming into training, and even in young horses when they're housed early on in life."

The researchers looked at a number of variables and found a significant environmental component. "The disease was more severe, and there was more airway inflammation, in horses that were exposed to high levels of endotoxin in their stables," reports McGorum. "Thus, endotoxin not only contributes to disease in older horses with heaves, but also can cause respiratory disease in younger horses. So, we need to be careful with air hygiene for all horses, not just older horses with heaves."

Performance

Racehorse data. Although the prevalence of low-grade lower airway inflammation in racehorses is known in Europe, no such data are available for U.S. racehorses. To remedy that, MSU researchers are completing a very large study at Thistledown racetrack in Cleveland, Ohio.

"We examined 150 horses each month over a two-year period at Thistledown," explains Robinson. Each month, the upper and lower airways of these horses were examined via endoscopy and graded by severity of disease. "We're also measuring mucus and counting inflammatory cells. Then we're going to look at that in relation to the horse's recent racing performance. When the data is re-analyzed, we should know the relationship for small amounts of airway mucus to inflammation and know if mucus accumulations are associated with reduced performance."

Pleasure and performance. Having set up the system to examine large numbers of horses at the racetrack, the MSU team is about to begin an investigation of the prevalence of airway inflammation in pleasure and performance horses in Michigan. Says Robinson, "This is necessary because there have been no such investigations in the United States. It is known that stabled horses in Europe have a high prevalence of airway inflammation. Are U.S. horses similar or are they outdoors enough that their airways remain quite healthy? If the research team discovers stables with a high prevalence of airway inflammation, they will conduct air quality measurements to see if there are pollutants that may be causing the problem."

Can arduous exercise in cold weather cause upper and lower airway inflammation and obstruction? That's what Michael S. Davis, DVM, MS, PhD, Dipl. ACVIM, associate professor at the Oklahoma State University College of Veterinary Medicine, and the director of the Equine Athletic Performance Laboratory at the same institution, is attempting to find out.

In humans, strenuous exercise in cold weather seems to create a form of exercise-induced asthma known as "ski asthma," as opposed to exacerbating pre-existing allergic asthma, Davis says. "The key features in the development of ski asthma appear to be the large increases in ventilation during exercise in very cold air. Since horses exercise in similar cold conditions as humans, and proportionately breathe harder, we suspect that they may also suffer from a similar syndrome."

To date, Davis' team has proven that even during relatively mild exercise, the initial stimulus (lower airway heat and water loss in the lower airway) is present in horses. "We have also demonstrated that this stimulus causes damage to the airway lining," he says. Davis is now determining whether these initial events ultimately lead to airway inflammation and obstruction. "If we can prove that this is an important cause of lower airway disease in horses, then horsemen will have good reason to consider the ambient exercise conditions when planning exercise or even competitive events."

(Funding for this research is through the Thoroughbred Charities of America, USDA, and National Institutes of Health.)

Diagnostics

New diagnostics. Two studies currently underway at the Centre for Equine Studies, Animal Health Trust, in Newmarket, England, are looking to 1) develop techniques that monitor the onset and time course of airway inflammation and the response to treatment, and 2) create simple, non-invasive approaches to screen horses for airway inflammation.

David Marlin, BSc, PhD, head of physiology at the Animal Health Trust, and visiting professor of respiratory and cardiovascular physiology at the University of Bristol in the United Kingdom, says many horses suffering from low-grade to moderate airway inflammation can remain undiagnosed for months or years; significant disease can be present even if clinical signs (e.g. nasal discharge) are infrequent or absent. Additionally, horses might not cough for several hours, then cough many times in a short period, then not cough again for hours, making it difficult for owners to pick up the coughing. If periods of inflammation are prolonged, irreversible lung damage can occur.

Until recently, the only sure way of knowing if a horse was free of lower airway disease was through endoscopy. But recently, Marlin's team developed another technique to screen for IAD by collecting and measuring the amount of hydrogen peroxide in the moisture of the horse's exhaled air.

"Hydrogen peroxide is produced by cells within the lung that form part of the immune system," says Marlin. "In the healthy lung, very little hydrogen peroxide is produced, but when there is inflammation either due to infection (bacteria or viruses) or allergic reactions to dust and molds, the cells of the immune system produce more hydrogen peroxide. In particular, the exhaled breath condensate hydrogen peroxide is increased in proportion to the numbers of particular inflammatory cells of the body's own immune system."

When an appropriate treatment is successful, the improvement is matched by a decrease in hydrogen peroxide. This approach might lead to easier and more frequent screening of horses, but is not intended to decrease or avoid the use of endoscopy, which will remain the gold standard for diagnosis, Marlin says.

Breathe deep and blow. Forced expiration is a sensitive test of airflow obstruction in horses with IAD and heaves, researchers at Purdue University have found. Explains Laurent Couetil, DVM, Dipl. ACVIM, associate professor of large animal/equine sports medicine, "We compared findings in healthy horses to those with IAD and heaves, either when they were in crisis or remission, and found we could detect fairly significant amounts of airway obstruction in horses with IAD. Obviously, horses with heaves in crisis had a dramatic reduction in the flow they were able to generate; more interesting was that heavey horses in remission--clinically asymptomatic--were also quite obstructed."

Couetil learned that quantifying the airflow out of a horse is a sensitive indicator of the severity of airway disease.

Deep breathing, going portable. Andrew M. Hoffman, DVM, DVSc, Dipl. ACVIM, associate professor of large animal medicine in the Department of Clinical Sciences at Tufts University, is trying to develop a pulmonary function test for use in the field to measure lung capacity and gauge pulmonary impairment. Asthmatic humans already have such a test, where humans blow into a machine to determine lung capacity (as do horses), but the currently available equine test can only be conducted in a laboratory.

"The new field test will enable assessment of hyper-reactive airways and would be readily applicable to foals or young athletic horses either in training or not, " Viel reports. When used on young, athletic horses, the test could be an indicator of future compromised lung capacity.

It's in the blood. Investigation into early detection of IAD continues at Purdue University. Says Couetil, "IAD is a much milder condition compared to chronic airway obstruction, so essentially the extent of pulmonary lesions are just milder. Therefore, much more sensitive tools are needed to detect abnormalities."

In racehorses, the blood oxygen level drops during strenuous exercise. Airway problems further decrease those oxygen levels during high-speed exercise, thereby limiting performance. Couetil learned that measuring the blood oxygen levels of a racehorse during standardized treadmill exercise is a sensitive gauge of IAD severity.

Treatments

Cheaper, better? Currently, corticosteroids are the treatment of choice for reducing inflammation caused by heaves. "There are multiple ways to administer corticosteroids," notes Robinson, "but the cheapest way is to give dexamethasone by mouth." Consequently, MSU researchers have been examining the efficacy and speed of onset of dexamethasone. "When dexamethasone is given by mouth, it is just as effective as by the intravenous route," says Robinson. "What is surprising is that dexamethasone causes a significant improvement within three to four hours. Previous studies had made the first measurements to try and detect an improvement three days after the start of treatment."

Better, part 2. At Kansas State University, Bonnie Rush, DVM, MS, Dipl. ACVIM, professor in the Department of Clinical Sciences and head of equine medicine and surgery, is investigating the efficacy of beclomethasone dipropionate for reducing inflammation and keeping airways open in horses with heaves. "Beclomethasone is a corticosteroid used in humans to treat asthma," Rush explains. "Heaves is an allergic condition similar to asthma in people."

Rush is seeking to identify duration of treatment, side effects, and appropriate dose. So far, she's found that administration of beclomethasone in an aerosolized form through the horse's nostril via an equine aerosol delivery device achieves much greater pulmonary drug delivery than either the mask system or inhaler devices. An aerosol delivery device is inserted into the horse's nostril, and when he inhales the handler squeezes to insert the medicine into the nasal passages. This compares to a mask or inhaler, which covers the horse's nostril(s), creating a seal. "It's about a three-fold improvement in drug delivery," she says. "You'd need to use about three times as much drug with a mask or inhaler in order to achieve the same results."

Rush hopes to see FDA approval for beclomethasone for the treatment of heaves in the next few years.

Long-term goals include investigating drugs for low-dose, long-term, daily use as a prevention for horses prone to developing breathing difficulties. "Humans use daily, low-dose drugs to prevent exacerbations of disease," Rush states, "and that's where I'd like to see these products eventually put to use. However, we need to answer the short-term questions before we can start to make applications for the long-term usage."

About the Author

Marcia King

Marcia King is an award-winning freelance writer based in Ohio who specializes in equine, canine, and feline veterinary topics. She's schooled in hunt seat, dressage, and Western pleasure.

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