Breathe Easier!

When Anne Thomas called me to her ranch house early one spring morning, she said it was urgent. Her 5-year-old horse, Charlie, was having trouble breathing. When I arrived at the barn, I could see the bay gelding standing in the middle of his paddock, and although I was 50 feet away, I could already see the problem. Charlie was standing still with his head and neck extended; with every breath his chest was expanding and contracting like a bellows, his nostrils flaring.

When Charlie exhaled his abdominal muscles tightened and lifted, showing the tremendous effort it took for him to push air out of his lungs. Charlie was suffering from an allergic reaction to something he had inhaled. I eventually made the diagnosis of heaves, also known as recurrent airway obstruction (RAO), and formerly called chronic obstructive pulmonary disease (COPD). (The term COPD is used in human medicine to describe a severe, progressive inflammatory lung disease that is particularly prevalent in smokers. Because there are some similarities between COPD in humans and heaves in horses, COPD was also used to describe the equine condition. However, research over 10-15 years has shown that the human condition and the equine condition are quite different; in fact, heaves in horses more closely resembles human asthma than human COPD.)

Anne was understandably upset and confused by the diagnosis. She couldn't understand how her horse could have a chronic illness when he was so young. She told me this was only the third time she had seen him like this, although this time was definitely the worst. The thought of facing breathing problems in her horse for the rest of his life was unimaginable, and she wondered aloud if he would still be able to work. It is never easy to hear that your horse is ill, but it is especially hard when the disease is difficult to understand, difficult to predict, and has no cure.

But Anne has reason to be hopeful. Over the past decade, our understanding of chronic lung disease has increased and a number of new drugs have emerged. New drugs that target the lungs more specifically, virtually eliminate many of the troublesome side effects of traditional therapies. And just as many human athletes with asthma can compete at the highest levels, so equine athletes and their owners might be able to achieve top performance despite a diagnosis of heaves.

The Immune System and Heaves

In order to understand the various treatments available for heaves, it is necessary to have a basic understanding of what can go wrong in a horse's lungs. The respiratory tract is a portal for bacteria, viruses, mold spores, and other harmful substances. The very deepest regions of the lungs are in close contact with the bloodstream and provide a ready path for infectious organisms to enter the body.

The respiratory tract, which starts with the nasal cavity and continues down the trachea and bronchi into the smaller airways of the lungs, must put up effective barriers to these invaders. This is accomplished by physical means, such as trapping contaminants in thick mucus, and through the actions of the immune system.

The problem in horses with heaves begins when the immune system overreacts to an inhaled contaminant. This overreaction is technically known as hypersensitivity and commonly known as an allergy. Although in theory anything floating around the air in the barn can trigger a reaction, mold spores are by far the worst offenders. Mold is almost unavoidable in hay--there can be more than 50 types of mold spores in baled hay. Depending upon the moisture content of the grass when it is harvested and baled, the interior of the bale might be prone to heating up. The combination of increased moisture and heat encourages mold spores to proliferate. Many mold spores are so small that they can travel deep into the chest and deposit themselves in the small airways of the lungs, triggering a local inflammatory reaction.

The immune system is designed to protect the animal, but when hypersensitivity develops, that protective mechanism can create an immediate crisis for the horse and lead to permanent lung damage if it is not adequately controlled.

There are several kinds of white blood cells in the lungs; the most prominent cell type in the lungs of horses with heaves is the neutrophil. These inflammatory cells release chemicals that cause the large airways to spasm and constrict, and the smaller airways to swell and plug with mucus. This, in turn, makes it very difficult for the horse to exhale--a hallmark of heaves. An affected horse has to literally force the air out of his lungs using his abdominal muscles, just the way Charlie did that day in the paddock.

Neutrophils and other immune cells called macrophages are also thought to release potent enzymes called matrix metalloproteinases (MMPs) that destroy elastic fibers in the lungs. Without these fibers, the lungs are less pliable, making it even more difficult for the horse to exhale. Over time, if MMPs and other destructive enzymes are allowed to continue unchecked, the lungs become stiff and scarred. When the horse is again exposed to molds, the resulting allergy attack will be even more severe.

Medical Treatments

Atropine is a drug that is used to treat a number of different medical problems in horses, such as uveitis (an inflammatory condition of the eye) and organophosphate pesticide poisoning. It is administered intravenously, so it has effects throughout the body, some of which are undesirable. These side effects include a rapid heart rate, dilated pupils, and general agitation and excitement. Atropine can also interfere with normal movement of the intestines, producing a condition called ileus (loss of normal intestinal motility) that can lead to colic. Another undesirable side effect is a decrease in the activity of the tiny hairs that line the trachea. These hairs (called cilia) move in rhythmic waves, passing excess mucus and debris up and out of the lungs. This isn't much of a problem for most horses, but might complicate things further for the heaves horse. Atropine can be very effective during a serious attack because it blocks the activity of the nerves in the respiratory system that cause bronchospasm. However, because of its side effects, it is usually only given once.

Glycopyrrolate, a cousin to atropine, is also administered intravenously, but has fewer side effects and can be administered once or twice during an acute attack. Another drug in this class, called ipratropium bromide, is formulated for human patients and can be administered by aerosol inhalation. Since inhalation therapy bypasses the rest of the body, this drug has virtually no side effects associated with its use. However, it doesn't tend to provide relief as rapidly as the other drugs in this class.

The Power--and Pitfalls--of Corticosteroids

Historically, the mainstays of treatment for horses with heaves have been strong anti-inflammatory medications called corticosteroids. These drugs, such as dexamethasone, are not the types of steroids that enhance performance. Rather, they block inflammation from several fronts, including the release of white blood cells. When these cells are kept in check, they are unable to release large quantities of the chemicals that cause swelling and bronchospasm.

Corticosteroids are very effective and tremendously useful for treatment of acute attacks in the heaves horse. Within six to eight hours of administration of these drugs, the horse will be visibly relieved and able to breathe much more comfortably.

For all of their usefulness, however, corticosteroids have a number of serious side effects and are not suitable for long-term control of heaves. The horse's body is extremely sensitive to the concentration of corticosteroids that are circulating in the bloodstream. When that concentration increases for several weeks in a row, the horse's adrenal glands will respond by slowing and even stopping the production of the natural steroid cortisol. In addition, should the horse receive too high a dose of corticosteroids for too long, the entire immune system can become depressed and unable to function normally. When this happens, the horse becomes susceptible to various infections, including pneumonia.

But of all the potential problems associated with corticosteroid therapy, perhaps the most feared complication is laminitis (founder) because it is difficult to predict and can have devastating consequences.

The good news is that the judicious use of corticosteroids to control acute attacks of heaves is not usually associated with any lasting problems. But there are still those six to eight hours to contend with before the medication can take effect. When you are watching your horse suffer with every breath, those hours can feel like an eternity.

Bronchodilators

Most people know at least one person with asthma and recognize those small canisters that asthmatics always carry with them. The introduction of inhaled bronchodilators revolutionized the treatment of asthma in humans. Now, instead of an automatic trip to the emergency room, an asthma attack can often be controlled with a few quick puffs from an inhaler.

There are several different classes of bronchodilators, each with a different mechanism of action and different routes of administration (see "Medications Used for Heaves" at left). What they all have in common is the ability to relax the smooth muscle cells that control the diameter of the airways, allowing them to dilate so that air can move more freely in and out of the lungs.

Bronchodilators have become an important component of heaves treatment in the horse. Obviously, delivering inhaled medication to horses is a little more difficult than in humans. In many cases, a mask is required to fit over the nose and mouth while the drug is aerosolized into a fine mist for inhalation. New inhalers created for horses mimick the ones used in humans and don't require a mask; these merely fit in the nostril of the horse.

Clenbuterol, terbutaline, and albuterol belong to a class of bronchodilators called beta-adrenergic agonists (or beta-2 receptor agonists). These drugs exert their effects on smooth muscle by binding to and stimulating a cellular receptor called the beta-2 receptor. The beta-2 receptor, when bound and activated, relaxes the smooth muscles in the airways, causing the airways to dilate.

Unfortunately, the beta-2 receptor is quite similar to another receptor, beta-1, which is found at other places in the body, including the heart. If too much of the drug is given, beta-1 is bound and activated--the horse experiences an increased heart rate, nervousness, sweating, and trembling, as well as possible ileus and colic.

Clenbuterol is a popular treatment choice of veterinarians. It can be administered orally; with careful dosing, side effects are minimal because clenbuterol tends to bind more readily to the beta-2 receptor than the beta-1. The effects of clenbuterol are relatively long-lasting (up to 12 hours). In addition, clenbuterol stimulates the activity of the cilia in the trachea, assisting the process of eliminating mucus and microscopic debris.

Terbutaline is available in the United States, but is only approved for the treatment of asthma in humans. Its use in horses is considered "off-label," but it is still used as a treatment for heaves. Terbutaline can be given orally, which makes it a nice choice for maintaining horses in the days after an acute attack has been brought under control.

Albuterol is another bronchodilator that is approved for treatment of human asthmatics, and it was recently approved by the Food and Drug Administration in the United States for use in horses with heaves. It can be administered by aerosol inhalation, which limits side effects but also limits its duration of activity (usually less than one hour). Albuterol can also be given orally, but studies have shown that it is simply not very effective by this route in the horse.

More Drug Therapies

Many asthmatics know that a couple of cups of very strong coffee in the morning can relax tightness in the chest. The bronchodilating effects of coffee are due to caffeine and its effects on the smooth muscles of the airways.

Aminophylline (and its activated form, theophylline) are chemically similar to caffeine and very effective oral medications in the horse, usually providing relief for six to eight hours. Unfortunately, there is a fine line between an effective dose and a toxic dose of these medications, making them somewhat tricky to use. When blood concentrations are too high, the horse can become very agitated, excited, and difficult to manage, somewhat like the human experience of drinking an entire pot of coffee.

Bronchodilators are an integral part of the management of heaves, providing immediate relief during an acute attack. However, unless the substance that triggered the attack is removed from the environment, another attack will be close at hand.

For this reason, efforts are now being focused on developing medications that help prevent acute attacks of heaves.

New Preventive Therapies

Inhaled Corticosteroids--In an effort to prevent repeated attacks, recent research has focused on inhaled corticosteroids that deliver a low dose of drug directly to the lungs. When corticosteroids are applied in this manner on a regular basis, the immune system is kept in check just enough to prevent many acute attacks.

In addition, inhalation eliminates the need for the drug to circulate through the bloodstream to reach its target. Therefore, many of the complications associated with oral and injected corticosteroids are simply not seen with inhaled steroids.

Two studies published in 1998 reported on aerosolized beclomethasone for heavey horses. The results were positive--ease of breathing significantly improved in treated horses. But after two weeks of treatment, there was evidence that beclomethasone was partially absorbed into the bloodstream and had suppressed the horses' natural secretion of cortisol, an effect similar to that seen with injected corticosteroids.

The following year, a paper was presented at the annual American Association of Equine Practitioners' convention reporting on another inhaled corticosteroid, fluticasone. In that study, horses were given fluticasone via an inhalation mask twice a day for three weeks. When the horses were exposed to moldy hay, there was virtually no reaction and no evidence that the fluticasone suppressed normal cortisol levels. This type of research into inhaled corticosteroids and other preventive medications is certain to continue (see "New Hope for Heaves Horses" on page 60) and so far looks very promising.

Management--You cannot over-emphasize the importance of managing the horse's environment. Even the best preventive medications won't help much if the horse is continually exposed to high levels of dust and molds.

One management technique might be to keep the horse at pasture if it is determined that pasture allergens are not the cause of the heaves. When this is impractical, steps should be taken to control the environment (dust and mold) in the stall and barn. If the horse can be kept in a small barn, more control can be achieved. In a large barn, efforts should be made to control conditions not only in the horse's stall, but also in adjacent stalls.

All horses require good ventilation, but it is especially important for horses with heaves. This means not only providing windows and fans, but also limiting the buildup of ammonia-releasing urine in the stall. High levels of ammonia are extremely irritating to the heaves horse, and might make him more susceptible to an attack.

Choose a stall that is far away from any manure piles if possible, and avoid overhead haylofts. In addition, straw bedding should be avoided. In its place, choose rubber mats, shredded newsprint, or high-quality wood shavings.

Perhaps the most simple management strategy is to eliminate baled hay from the heavey horse's diet. Encourage grazing whenever possible, and switch the horse to cubed or vacuum-packed hay products. Many horse owners soak hay prior to feeding it to their heaves horses. This can be effective, but usually only for milder cases.

It is important to remember that if the horse in the stall next door is being fed baled hay, all of your efforts might be in vain. Therefore, whenever possible, enlist the help of owners of neighboring stall inhabitants and barn personnel in all control measures. Remember that the idea is to lessen exposure to irritants and allergens so that any necessary medications prescribed by your veterinarian will work more effectively.

In the end, Charlie had a good outcome. His owner was able to move him to a farm where he could be kept entirely at pasture. He was managed on a pelleted feed, and with the judicious use of steroids and an oral bronchodilator, he was able to continue as an active trail horse. His owner was relieved to discover that a diagnosis of heaves did not bring an end to their working relationship.


NEW HOPE FOR "HEAVEY" HORSES

The search for a lung-specific treatment for heaves has led to the investigation of a group of drugs called leukotriene inhibitors. Leukotrienes (LTs) are one of the foot soldiers of inflammation. Inside the lungs, an enzyme called 5-lipoxygenase metabolizes a large fatty acid, arachidonic acid, to produce an array of LTs. The LTs are named in alphabetical order for the sequence in which they are produced from arachidonic acid. Some of these, including LTB4 and LTD4, produce the swelling and airway spasm associated with heaves in the horse. These LTs also attract neutrophils to the area, which release their own inflammatory chemicals, compounding the reaction.

Two classes of LT inhibitors are being investigated for use in horses. Drugs in the first class inactivate the enzyme 5-lipoxygenase, preventing LT formation at the source. The second class of drugs prevents LTD4 from binding to cells in the airways. Clinical trials of a drug called fenleuton, a 5-lipoxygenase inhibitor, have been performed in horses with promising results.

In one study at the Royal Veterinary College in Hertfordshire in the United Kingdom, horses were treated with fenleuton prior to being challenged with moldy hay. While fenleuton treatment did not prevent the accumulation of neutrophils in the lungs, it did significantly lessen bronchoconstriction after the hay challenge. In addition, the amount of airway relaxation was similar to what is seen with bronchodilator therapy. Leukotrienes are still in the investigational stage, but might provide another weapon in the arsenal for the war against heaves.

Chemically Modified Tetracycline

Tetracyclines are antibiotics that are used to treat a number of different infections. Studies have shown that tetracyclines also have effects beyond their antimicrobial activity. These effects include inhibition of matrix metalloproteinase (MMP) enzymes, which are known to have adverse effects on the joints of horses with osteoarthritis. Matrix metalloproteinases have also been implicated in the destruction of elastic fibers in the lungs of heaves horses, leading some researchers to wonder if tetracyclines could be effective in the management of chronic lung disease.

It is possible to modify the tetracycline molecule, removing its antimicrobial abilities but retaining its other useful functions. Chemically modified tetracyclines (CMTs) are already being used in human medicine to protect the lungs after a patient has been placed on cardiopulmonary bypass, also known as the heart-lung machine.

A group of researchers in Finland recently examined the effects of these drugs on MMPs in lung fluid from horses with heaves. They discovered that CMT did indeed decrease MMP activity in the fluid. This work is only preliminary, but there is hope that these drugs will one day provide some relief for the heaves horse, perhaps lessening the amount of other medications needed to keep the disease in check.--Susan Piscopo, DVM, PhD

MEDICATIONS USED FOR HEAVES
DRUG CLASS
GENERIC NAME
ROUTE OF ADMINISTRATION
Anticholinergics

Atropine
Glycopyrrolate
Ipratropium bromide

intravenous
intravenous
aerosol

Beta-2 Receptor Antagonists Clenbuterol
Terbutaline
Albuterol

oral
oral
aerosol, oral

Phosphodiesterase Inhibitors Aminophylline
Theophylline

oral
oral

About the Author

Susan Piscopo, DVM, PhD

Susan Piscopo, DVM, PhD, is a free-lance writer in the biomedical sciences. She practiced veterinary medicine in North Carolina before accepting a fellowship to pursue a PhD in physiology at North Carolina State University. She lives in northern New Jersey with her husband and two sons.

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