Heartworm

• The Parasite
• Canine Heartworm Disease
• Epidemiology
• Clinical Signs
• Testing
• Prevention
• Treatment
  

THE PARASITE

When adult male and female worms are present, mating begins to occur. Heartworms do not lay eggs like other worm parasites; instead they give live birth and the baby worms are called Microfilariae. Mosquitoes are the only natural carriers of the heartworm. The life cycle of the heartworm begins when an infected dog carrying the tiny immature heartworms circulating in its blood, is bitten by a mosquito and carries it to a new dog.      

Microfilariae may live up to two years within the host dog in whom they were born; if after this period a mosquito has not picked them up, they die of “old age.” They may also be transmitted across the placental barrier to unborn puppies if the mother dog is infected with heartworm. It is important to realize that such puppies will not develop adult heartworms or heartworm disease from these microfilariae because in order for a heartworm to reach adulthood, it must be passed through a mosquito. Because of the five month minimum migration time of the larval heartworm after infection, there is no point to heartworm test puppies younger than five months of age.

Parasitic worms have 5 larval stages and are termed "L1", "L2", "L3", etc. Heartworm microfilariae are first stage larvae: L1's. Within the mosquito's body, the microfilariae will develop to L2’s and finally to L3’s, which is the stage capable of infecting a new dog. How long this takes depends on the environmental conditions. In general, it takes a few weeks. A minimum environmental temperature of 57 degrees F is required throughout this period. The process goes faster in warmer weather.

CANINE HEARTWORM DISEASE

The adult worms live in the heart and lungs and their microscopic offspring, the microfilaria, are in the bloodstream which eventually reach the dog’s heart. Once in the dog’s heart, the worms grow and cause significant damage to the heart, lungs and other vital organs. The adult heartworm (Dirofilaria immitis) is a fairly large worm (up to 14 inches long) that, in adulthood, lives in the heart and pulmonary arteries. It swims into an artery, where it is massaged and nourished by the blood coursing past it. In the pulmonary arteries, the worm's presence generates a strong inflammatory response and a tendency for blood to inappropriately clot. If enough worms are present, the heart must work extra hard to pump blood through the worm-filled arteries.

If the worm infection is a heavy one (over 25 worms for a 40 lb dog), the worms begin to back up into the right ventricle (the chamber which pumps blood through the lung). The worms actually take up a significant amount of space within the heart, leading to less blood being pumped.

Heartworms are transmitted by over 70 species of mosquitoes. The disease is primarily associated with dogs but also occurs in foxes, coyotes, sea lions and domesticated cats. Wherever mosquitos live and breed, dogs are at risk. Those that live out in the country or spend a significant amount of time outdoors, are most at risk. Because of this it is recommend that all dogs be on a course of heartworm prevention. The preventative kills the heartworms before they mature, keeping the worms from clogging the dog's heart and blood vessels.

EPIDEMIOLOGY

• Types of mosquitoes capable of carrying larval heartworms.
• The weather must be warm enough to allow larval development in the mosquito
• There must be infected animal in the area
• There must be vulnerable dog dogs in the area

CLINICAL SIGNS

Heartworm disease may cause combinations of medical problems within the same dog including dysfunction of the lungs, heart, liver and kidneys. The disease may have an acute onset but usually begins with slow barely detectable signs resulting from a chronic infection with a combination of physiologic changes. Dogs with a low number of adult worms in the body that are not exercised strenuously may never have overt signs of heartworm disease. The heart and lungs are the major organs affected by heartworms in dogs with varying degrees of clinical signs.

Clinical Signs Associated with Canine Heartworm Disease:

• Early Infection
  No abnormal clinical signs observed
• Mild Disease
  Cough
• Moderate Disease
  Cough, exercise intolerance, abnormal lung sounds
• Severe Disease
  Cough, exercise intolerance, dyspnea (difficulty breathing), abnormal lung sounds, hepatomegaly (enlargement of the liver), syncope (temporary loss of consciousness due to poor blood flow to the brain), ascites (fluid accumulation in the abdominal cavity), abnormal heart sounds, death

Arteries do not do well having worms living inside them. The lining of the artery becomes damaged within days of the worm's arrival. Cells of the immune system are called into the area but the worm is far too big for these tiny cells to destroy. The resulting inflammation continues to damage the artery. With the arteries plugged with worms, the heart must pump harder against the pressure of the plugged arteries. This condition is called "PULMONARY HYPERTENSION " and the right side of the heart must drastically increase its ability to work.The heart may be strong enough - and it may not. The arteries dilate and become tortuous (which may be visible on a radiograph). Aneurysms and abnormal blood clotting (embolism) results. Blood is shunted to other arteries which are not plugged up by worms and fluid begins to accumulate in the lung around the worm-filled arteries. Blood sent to the lung is not sufficiently oxygenated and areas of the lung become consolidated and are unable to provide oxygen to the blood. Coughing and exercise intolerance result as areas of the lung are lost to the blood oxygenation process. Nose bleeds may occur due to abnormal blood clotting in the lung. A form of non-infectious pneumonia ("pulmonary eosinophilic granulomatosis") can result from excessive infiltration of inflammatory cells into the lung in response to the parasite.

If worms begin backing up into the heart, there will be less space in the pumping chamber for blood to be pumped. The heart must pump through the high pressure system of the plugged arteries using less blood then normal. In order to meet the body's oxygen demand, the heart must pump faster and stronger still. There may come a point when the heart simply is not strong enough.

When the heart muscle begins to thicken (as any over-worked muscle will), it may not conduct electrical impulses normally. This means that the pumping/filling rhythm can be disrupted and an "ARRHYTHMIA" may result. If the right side of the heart becomes too weak to keep up, fluid may accumulate in the chest cavity and abdominal cavity, leading to a pot-bellied appearance and/or difficulty breathing. When a dog goes without treatment for heartworm disease, its immune system becomes chronically stimulated. Antibodies, which are not only important tools of the immune system but are inflammatory proteins, are produced in high amounts all the time. These antibodies can cause a lot of trouble by precipitating in the delicate membranes of the eye, kidney, blood vessels, and joints. Antibodies stuck in these areas, attract inflammatory cells and damage these delicate membranes thus setting up tremendous tissue damage and pain.

Caval syndrome represents an especially disastrous form of heartworm disease. Here, there are so many worms present (around 100) that the entire right side of the heart is filled with worms and they are backing out into the large veins that feed the right side of the heart. Usually there have been no signs of heart disease prior to the collapse, shock, and red blood cell destruction associated with this syndrome. Death usually occurs within 1-2 days and the only effective treatment is to open the dog's jugular vein and physically remove the worms with a special clamp. If enough worms can be removed to re-establish blood flow, the dog may survive. Heartworm disease is a highly significant problem and must be managed both by dealing with the worms and by dealing with the heart disease.

TESTING

There are different types of blood tests that are used to determine if your pet has heartworms. The filter test involves taking a blood sample and looking to see if any microfilaria show up under a microscope. While this method is a simple screening test, it is not recommended as a regular test method. In this test, a single drop of blood is examined under the microscope for the presence of live microfilariae. If a large number of microfilariae are present, chances are at least one will be seen seen swimming by. Of course, detection of heartworm larvae in this way require large numbers of larvae for detection (less than 20-50 microfilariae per ml of blood will not be detected). More subtle infections will be missed.

Another type of blood test looks for antigens (foreign proteins) given off by the heartworms. This test can reveal the presence of heartworms that the filter test might miss because the heartworms aren't reproducing. The chief issue in the diagnosis of heartworm disease centers around the detection of heartworm infection. Using genetic engineering, it has become possible to create extremely sensitive tests capable of detecting tiny pieces of adult heartworm skin circulating in the blood. In this way, very small numbers of adult worms can be detected, even single worm infections. This kind of testing has made it possible to detect infections in which no microfilaria are present: the "Occult Infections." Most of these immunological tests are available as test kits which can be performed in the veterinarian's office while you wait.

Antigen tests have limited usefulness when it comes to infections involving only a few worms. One problem is that the antigens detected by antigen tests are unique to female worms. For most tests, at least three female worms are needed for the test to show a positive result. Animals infected with only male worms will test antigen negative. To get around these limitations, antibody tests have been developed to detect the dog's immune response against the parasite. This kind of breakthrough has been especially important in testing for cats in whom infection with one or two worms is the usual situation. Antibody testing may be able to detect infection sooner than can antigen testing and infections involving only male worms can be readily detected.

In areas where heartworm infection is not common, routine testing is not performed and infection is unlikely to be detected until the dog is sick. In these cases, the infection is picked up during the work-up for heart disease. Radiographs can be strongly indicative of heartworm infection if they show blunted tortuous pulmonary arteries and enlargement of the right side of the heart (the side doing all the extra work to pump blood past the worms). Ultrasound not only can measure thickening of the right side of the heart but can actually show the live worms wiggling.When imaging tests are consistent with heartworm disease, antigen and/or microfilaria testing would be the obvious next step.

Heartworm is not the only species of worm that has circulating microfilariae as a first stage larva. There is another parasite called Dipetalonema reconditum, which is transmitted by fleas, which may be picked up by the microfilaria tests. Subtle differences in the swimming characteristics, nose structure, and tail structure can be used to distinguish this harmless larva from the more serious heartworm microfilaria.Before immunotechnology, there was an element of diagnostic challenge when microfilaria were detected in the blood (was the nose the shape that would justify a harsh and possibly life-threatening treatment for heartworm infection or was it a harmless creature for which no treatment was needed?) The advent of antigen testing has made this distinction much easier to make.

The Difil and the Knott's tests are concentration methods for the detection of microfilariae. In these tests, a larger amount of blood is either centrifuged or filtered to concentrate any microfilariae present. When a microfilaria test is to be done, either of these would be appropriate. Nowadays, microfilaria testing is usually done in conjunction with antigen testing.

A dog might be infected with adult heartworms yet no microfilariae can be detected. If all the heartworms present are of the same sex, no microfilariae will be present. Younger female worms tend to be resistant to the drugs used to clear adult worms. This means that after the first treatment with anti-heartworm medication, a group of young female worms will be left. If antigen testing is not performed one could be misled into thinking that the infection had been completely cleared.

Both Interceptor and Heartgard30 are able to kill circulating microfilariae (but not adult heartworms). If for some reason, a dog is not properly tested and has missed a dose of medication, it is possible for an infection to establish yet no microfilariae will be detected. People commonly ask why they must continue annual testing in animals that are on preventive medication; this is one reason.

Since Dipetalonema microfilariae can be mistaken for heartworm larvae and since microfilariae can be transferred to unborn puppies (but adult heartworms cannot), it is felt by many specialists that no microfilaria positive dog should be treated for heartworm without a positive antigen test.

An important basic concept in the treatment of heartworm infection is that there are adult heartworms in the heart and pulmonary arteries to be killed and there are microfilariae circulating in the bloodstream to be killed and one medication cannot be used to do both jobs. Heartgard30 and Interceptor, the main heartworm preventives available commercially, will kill microfilariae. Dogs on heartworm preventive, even if infected with adult heartworms, will not test positive for microfilariae. L3's are readily killed by Interceptor but not by Heartgard30. Interceptor and Heartgard30 both act primarily on the L4's living in the skin. After a dose of either medication, any L4's present will be wiped out. Heartgard30 is also able to kill the younger L5's.

 DIETHYLCARBAMAZINE (FILARIBITS made by Pfizer). Diethylcarbamazine, known as “DEC” and sold under the trade name Filaribits, must be given daily to prevent heartworm infection. It acts by killing L3’s and L4’s before they develop further and begin their migration into the vasculature. This approach is started right at the start of the mosquito season and must be continued for sixty days after any frost, or it may be continued all year. However, you must be aware that forgetting to give your pet his daily treatment for a day or two during the height of the mosquito season could possibly put your pet at risk. If you chose to use this treatement method, your pet should have a filter test done before starting on heartworm preventative, as an infected pet can develop an anaphylactic reaction. This means a negative heartworm test is a must before beginning the use of this medication. DEC does nothing against other common parasites but is available with Oxybendazole added (Filaribits Plus) to control hookworms, whipworms, and roundworms.

IVERMECTIN (HEARTGARD30 made by Merck) represented a huge breakthrough in heartworm prevention. Preventive medication for the first time could be given once a month instead of daily. This medication utilizes an extremely low dose of ivermectin which is adequate to kill any L4’s which are inhabiting the pet’s skin tissues at the time the medication is given. In other words, infection takes place but is halted every month when the medication is administered.

If ivermectin is inadvertently given to a heartworm infected dog with circulating microfilariae adverse reactions would not be expected; in fact, this product is commonly used in the treatment of active infection to clear microfilariae safely. This means, however, that giving this product to a dog with heartworm will kill all circulating microfilariae and the dog will test erroneously heartworm negative by Difil or Knott’s testing. In addition to killing microfilariae, ivermectin will also suppress reproduction in the adult female worms.

There is also a phenomenon called the “Reach back effect.” This means that if a dog goes off heartworm preventive medication for a prolonged period (four months was the time tested), re-starting ivermectin could still prevent adult heartworms from developing in the heart. Ivermectin at the heartworm preventive dose is not strong enough to kill common intestinal parasites but it is available with pyrantel pamoate included (Heartgard30 PLUS) to control hookworms and roundworms.

There are breed related sensitivities with ivermectin (i.e. collie-related breeds have some difficulties) though at the very low doses used in the prevention of Heartworm disease are not a problem for any breed. (Note that Merck has selected Lassie as the “posterdog” for their products).There have been numerous discussions about the safety, or lack of safety, of using ivermectin-based heartworm prevention in collies and other herding breeds of dogs. You should ask the breeder of your collie if a sensitivity to Ivermectin has been noticed.

Much of the concern over the safety of ivermectin began when this medication was first tested in dogs for toxicity studies. In the initial testing of ivermectin, the drug was tested in Beagles to see at what dose clinical signs of toxicity would develop. Later, these same studies were performed on Collies and it was found that Collies had clinical signs of toxicosis at much lower doses of ivermectin than the Beagles did. Therefore, at the time, a warning was issued that collies and collie mixes should not be given the newly approved heartworm preventative containing ivermectin as the active ingredient.

After these initial toxicity studies were done, further studies were done to determine if the dose of ivermectin present in the monthly medication would cause a problem in collies. As a reference, the dose of ivermectin in Heartgard is 6 - 12 micrograms per kg of body weight. In studies that have been done, doses of more than 50 micrograms per kg have been tested in collies to determine toxicity at many times the dose in Heartgard.

The signs of toxicosis seen in clinical trials varied in their severity. Early signs of toxicosis included salivation, dilated pupils, vomiting, tremors, and difficulty walking (ataxia). Severe signs of toxicosis included weakness, inability to stand (recumbency), nonresponsiveness, stupor, and coma.

In several of these type of studies, there were collies that seemed to react to ivermectin, and other collies that did not react to the ivermectin. It has been suggested that there are collies that are "ivermectin sensitive" and those that are considered to be "ivermectin non-sensitive" based on the results of these studies. Unfortunately, to date, no research has provided us with the ability to differentiate between the ivermectin-sensitive and non-sensitive collies.

Despite the studies being done, Ivermectin is not considered safe for collies by most breeders. Although Merck has recently removed its warning, there are now several cases of toxicity reactions reported from collies given Ivermectin. There have also been numerous reports of subclinical toxic reactions from dogs given Heartgard preventative. It is thought that there may be a wider range of sensitivity than indicated by the trials. The drug can be very toxic to Collie, Border Collie, Australian Shepherd, and Collie cross dogs. Therefore great consideration should be used in treating these breeds with an Ivermectin based preventative. To be completely safe, Collies and collie breeds should be given either carbamazine heartworm preventative (daily dose), or the monthly Interceptor heartworm preventative.

MILBEMYCIN OXIME (INTERCEPTOR & SENTINEL made by Novartis) is the chief competition of Heartgard30. This product is also given monthly, also clears microfilariae, acts by killing all L3’s and L4’s accumulated in the month prior to administration, and will suppress female worm’s ability to reproduce. There are a few important differences to note, though. If milbemycin is inadvertantly given to a dog with active heartworm disease, the dog may experience a serious shock syndrome if an especially high number of microfilariae are circulating.

When milbemycin is given to a dog after a prolonged period without heartworm preventive, the dog can be expected to have fewer heartworms than if heartworm preventive were not restarted. This was not as good a result as with the ivermectin product as the ivermectin product is better able to kill young adult heartworms. Milbemycin, however, is able to control roundworms, hookworms, and whipworms without the addition of a second parasiticide. It is also available combined with Lufenuron for the control of fleas. There are no breed- related sensitivities for milbemycin. Milbemycin oxime is also used effectively in the treatment of demodectic mange.

MOXIDECTIN (PROHEART made by Fort Dodge) is a derivative of ivermectin and the same rules that apply for Heartgard30 should apply to this new product. As is Heartgard30, ProHeart is a monthly tablet available in a 6-tablet package.

HOW OFTEN SHOULD A DOG BE TESTED?
If your dog is to begin taking a daily heartworm preventive ( Filaribits), life-threatening reactions can occur if this dog has circulating microfilariae at the time medication is started. Dogs using this product should definitely be tested annually. With differences in weather patterns every year (i.e. early Spring one year, late freeze another year etc.), it becomes difficult to figure out in what month heartworm preventive medication should be initiated. If there is any question about when the last possible transmission date was in the previous season, it is probably a good idea to simply test the dog annually. If there is any question about the dog spitting out any preventive tablets last season, then the dog should be tested before beginning prevention the next season. If the dog consistently takes monthly heartworm preventive medication all year round, then testing can probably be performed every 2-3 years (though an annual physical exam is needed to legally obtain a prescription for medication). If a dog lives in an area considered not to have heartworm and travels to an area that IS considered to have heartworm, both microfilaria and antigen testing should performed at least seven months after the last day the dog was present inthe heartworm endemic area.

TREATMENT OF THE INFECTION

Heartworms live in the heart and the large blood vessels which go to the lungs from the heart. When they are killed by medications, a danger of embolism results if the dead worms block the flow of blood to the lungs. This is a common cause of death during a heartworm treatment. Prior to therapy, the dog is assessed and rated for risk into one of four categories. Important factors include: how many worms are thought to be present based upon the tests performed, the size of the dog, the age of the dog, concurrent health factors, severity of the heart disease, and the degree to which exercise can be restricted in the recovery period. Some hospitals use computerized formulas to categorize heartworm infected patients. The important concept to realize is that very harsh arsenic based drugs are necessary to kill adult heartworms and that treating for heartworm infection is neither simple nor safe in itself.

The categories into which patients are grouped are as follows:

Group I: Lowest Risk. Young healthy dogs with minimal disease evident on radiographs, normal blood work, and no symptoms of illness.

Group II: Moderately Affected. Some coughing, moderate radiographic changes but normal bloodwork.

Group III: Severely Affected. Dog is suffering from weight loss, cough, difficulty breathing, blatant damage to the vasculature is apparent on radiographs, bloodwork reveals kidney and/or liver damage.

Group IV: Caval Syndrome. Dog is collapsing in shock with dark brown urine evident. Heartworms visible by ultrasound in the AV valve of the right side of the heart, very abnormal bloodwork. These dogs, as mentioned previously, are dying and can only be saved by the physical removal of adult heartworms via an incision through the jugular vein. If such a dog can be saved from this crisis, further heartworm infection treatment cannot be contemplated until the dog is stable enough to fit into one of the other categories.

THIACETARSAMIDE (CAPARSOLATE made by Rhone) has been the mainstay against adult heartworms for over half a century. It is a harsh drug (actually a derivative of arsenic) with the potential for serious life-threatening liver side effects. It is administered intravenously yet if any of it should leak outside of the blood vessel, a severe erosive tissue reaction occurs leading to tissue sloughing. It is typically given in two doses on each of two consecutive days. Younger adult worms of either sex and adult female worms tend to be somewhat resistant to this medication which means that a second course of treatment is likely to be needed to clear all the worms.

It is also important to realize that the death of a large number of heartworms at the same time will induce abnormal clotting and inflammatory reactions.These reactions typically become evident in the month following treatment and minimized exercise is very important.

MELARSOMINE DIHYDROCHLORIDE (Immiticide made by Rhone) Because of the toxicity potential of Thiacetarsamide, much research has been devoted to the development of a safer anti-heartworm medication. Melarsomine dihydrochloride represents the result of this research. This medication, which is also an arsenic derivative, is given deeply in the muscle by injection rather than intravenously and one treatment on two consecutive days is typically given. Dogs with large numbers of worms commonly receive one treatment to lower worm numbers and then several months later will receive the two day course. Muscle soreness and inflammation is common after treatment. Melarsomine appears to be substantially more effective at killing adult worms than Thiacetarsomide and is not toxic to the liver though, again inflammatory and clotting reactions may occur as the worm die off after treatment. Exercise restriction is still a good idea after therapy.

OTHER MEDICATIONS
With all the inflammation associated with the death of heartworms, medication to relieve inflammation may be needed. The obvious medication would be prednisone or a similar corticosteroid. However, the use of these medications seem to be protect the heartworms one is trying to kill. This is an unfortunate trade-off but is at times a necessary one. Many specialists instead prefer aspirin as a drug to help ease the inflammatory burden during the period of heavy worm death. There is much argument among experts regarding the importance of aspirin in the treatment of heartworm infection.