Feline Dirofilariasis

Feline Dirofilariasis

FELINE INFECTIOUS DISEASES 0195-5616/93 $0.00 + .20 FELINE DIROFILARIASIS Robert A. Holmes, DVM, PhD Ask the animals and they will teach you ... JO...

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FELINE INFECTIOUS DISEASES

0195-5616/93 $0.00 + .20

FELINE DIROFILARIASIS Robert A. Holmes, DVM, PhD

Ask the animals and they will teach you ... JOB 12:7

You must ask the right animal-the cat does not respond to heartworms as does the dog. Seek and you shall find ... MAlT. 7:7

Seek Seek Seek Seek

and you shall find-if they don't see you first; x-ray signs and you have the best chance of finding; antigen long enough and you may find-50 to 70% of the time; microfilaria and you will find-20% of the time.

As these quotes state, when you want to find heartworm disease in cats, the proper questions must be asked-then, you will have a chance of finding heartworm disease in cats. Although heartworm disease is usually thought of primarily as a disease of dogs, the cat is also a definitive host, because the life cycle of heartworms can be completed within the cat. The increased number of cases of feline heartworm disease seen can be attributed to several factors. The number of cats that are now household pets is increasing. As a result, more attention by the owner is paid to the everyday maladies of the cat. As knowledge is gained, veterinarians are now more aware that the cat is not like a dog in the way it responds to an invasion of infective heartworm larvae. The cat is a unique animal, and even though we know how the dog responds to heartworm disease, the cat responds differently; the From the Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 23 • NUMBER 1 • JANUARY 1993

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differences must be recognized and defined in order to make a definitive diagnosis. The geographic range of cases of heartworm disease in the cat parallels that of the dog, but the incidence level is lower. Over the years, the spread of heartworm disease in dogs has been recognized, therefore, the number of cases of heartworm disease in the cat probably has grown proportionately, but we just haven't recognized the trend. This discussion is intended to help recognize the unique features of heartworm disease in the cat. CLINICAL PRESENTATION

One of the main problems in the diagnosis of feline heartworm disease has been the vague general signs shown by the cat. The range and duration of signs are variable. A cat may be totally asymptomatic and then die from heartworm disease within an hour. Other cats may show clinical signs for a short period of time and then become apparently normal. Yet another group of cats may show low-grade, chronic signs. In general, the common signs for the acute case may include collapse, dyspnea, convulsions, vomiting, diarrhea, blindness, tachycardia, and syncope. Cats with the more chronic disease may show coughing, vomiting, dyspnea, lethargy, anorexia, and chylothorax. 1 Cats react more severely to the initial invasion of the cardiovascular system by the L5 larvae or young adult heartworms than dogs. These changes may be seen angiographically as early as 75 to 90 days after inoculation of infective larvae. Therefore, the acute clinical signs of heartworm disease could be seen as early as 75 to 90 days after initial inoculation. As a result of studies7• in Louisiana, Florida, and Georgia, it is now known that heartworm transmission during the months of December through March (Fig. 1) does not occur. Peak transmission period is late spring and early summer; there is then a steady decline in transmission extending until December. An examination of the medical records at Louisiana State University Veterinary Teaching Hospital and Clinics and an exclusive feline practice in Baton Rouge, Louisiana, showed that most cats were presented in the late summer or early fall. These are probably cats that were exposed during the spring or summer, and at the time of presentation, the larvae were in the cardiovascular system, causing vasculitis and pneumonitis. Pulmonary parenchymal disease may not be seen for another month after this stage. During this time, clinical signs could advance. If the cat survives the initial invasion and some heartworms survive, more chronic signs will be seen. Coughing and dyspnea are obviously cardiopulmonary related, but pulmonary hypertension as seen in the dog is not as readily apparent in the cat. Because adult heartworms live an average of 2 years in the cat as opposed to 5 years or longer in the dog, there may be resolution of clinical signs from a self cure in the cat. DIAGNOSTIC METHODS

In general, the diagnosis of heartworm disease in cats is more difficult to make than in the dog. Several methods are used commonly by veterinarians when canine heartworm disease is suspected. Algorithms for the diagnosis of heartworm disease in dogs and cats are shown in Figures 2 and 3. The algorithms are not absolute but represent a typical set of diagnostic procedures for a "simple" case of uncomplicated canine or feline heartworm disease. The diagnosis of heartworm disease is usually made during two types of

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TRANSMISSION SEASON

DEC

Figure 1. The transmission season begins and has the highest transmission in April and steadily declines through the summer months. There is apparently no transmission from December through March. Even though there are cases of heartworm disease in cat presented throughout the year, most cases are clustered in the late summer and early fall.

clinical presentations. Many dogs are checked for circulating microfilaria w ith a direct blood smear, modified Knott's test, or a filtration concentration test during the annual vaccination/fecal/heartworm regime . In heartworm endemic areas, this is usually an ingrained procedure that most clien ts readily accept as the minimum standard of preventive health care for the dog. However, this is an unusual process in the cat, as the microfilaremia examinations are not rou tinely done at vaccination time. The second type of clinical presenta tion for the dog is for medical reasons . A dog will be presented for problems such as dyspnea, lethargy, hemoptysis, and, if in an endemic heartworm area, heartworm disease is probably high on the list of possible diagnoses. The cat, on the other hand, may be presented for similar problems, but clinica l signs may be much more nebulous and may be confused with other common feline complaints . The traditional methods of detecting microfilaremias in dogs (i. e. , direct smear, modified Knott's test, or filtration concen tration test) will be rewarding in the cat no more than 20% of the time.' At best, the number of circulating microfilaria will be low and ephemeral. The possibility of a unisex population, low fecundity, low numbers of both male and female heartworms, or immature male or female heartworms contributes to the low numbers of microfilaria seen. Even if produced, microfilaria often are sequestered in other parts of the body and do not circulate for extensive p eriods of time . Serologic testing is an important component of the diagnostic scheme for heartworm disease in either the dog or cat. Several different types of serologic tests have been available to the veterinarian over the years, but only the commercial test kits for heartworm antigen are being used. The indirect

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fluorescent antibody test (IFA) is a reliable method of detection if sufficient serum antibody is produced. The IFA test was the first practical serologic test to be done, but it is not generally recommended for use at this time. One problem with the IFA test is that the infection must be of sufficient duration and magnitude to produce detectable antibody. Also, the test goes beyond the capabilities of most veterinarians, because they do not have a fluorescent microscope available. The next step in the quest for a reliable, simple test for heartworm antibody

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Figure 3. This diagnostic algorithm represents a method that could be used for a "simple" case of heartworm disease in the cat. *Knott's or filtration concentration.

was the enzyme-linked immunosorbent assay (ELISA). As with the IFA test, the ELISA tests are not diagnostic until there is enough circulating antibody produced. Additionally, there is cross-reactivity with other nematode parasites, and sensitivity and specificity of the ELISA test is not sufficient to distinguish between true positives and negatives and false positives and false negatives. Therefore, the ELISA test results were seldom definitive in the veterinarian's mind, and the ELISA test became just another piece of the diagnostic puzzle that was subject to interpretation. The next step followed in the serologic diagnostic pathway was the ELISA

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antigen detection method. The premise for the ELISA antigen detection test, as opposed to the antibody ELISA test, is that a heartworm excretes or secretes antigen more reliably than the host builds sufficient antibody to the heartworm. As with the serum antibody tests, the antigen tests also have their limitations. As the heartworms secrete antigens, the number of worms present determines, to a large degree, the quantity of antigen available for detection. The ELISA antigen tests are, therefore, worm burden dependent. That is, the greater the number of heartworms, the greater the amount of antigen that can be detected. In single-worm infections, only the female heartworm produces antigen and may, therefore, be detected, as opposed to an infection with one male heartworm, which would not be detected. Hematology would probably be the next diagnostic step. As with other methods, the hemogram alone may not be diagnostic. In about one third of the cases, dogs may show a mild nonregenerative anemia and eosinophilia. An eosinophilia might also be due to the somatic migration of roundworms or hookworms or other tissue-migrating parasites. Allergic conditions also must be considered with an eosinophilia. The presence of a basophilia adds credence to a diagnosis of heartworm disease in dogs and cats. 1 · • At this point in the diagnostic approach, thoracic radiography in the dog should be considered. Radiography can be used as a diagnostic or prognostic tool. When history and clinical signs direct the veterinarian towards heartworm disease but there is amicrofilaremia and no circulating antigen, then thoracic radiography become the prime diagnostic tool. If there is either microfilaremia or antigenemia along with clinical signs, thoracic radiography becomes more of a staging or prognostic tool. Thoracic radiography should be done to assess the degree of right ventricular enlargement, the degree of pulmonary trunk and peripheral pulmonary artery enlargement, and the presence and degree of interstitial and/or alveolar pulmonary parenchymal densities. •· 7 Although the degree of changes in the thorax is not an accurate indicator of the actual number of live heartworms or the probability of treatment complications, radiography will determine the amount of damage present in the cardiovascular and pulmonary systems. If the radiographic changes are minimal, the client can be advised that the probability of complications such as thromboembolism is small and that there is a good possibility that the cardiopulmonary damage can be reversed. On the other hand, if the clinical signs are severe and there are severe cardiopulmonary changes radiographically, the client might be advised that treatment should be done but the chances of thromboembolism are great, or that treatment should be delayed until the dog can be stabilized; possibly, aspirin or corticosteroids should be prescribed. Nonselective pulmonary angiography is a technique that is rarely done in private practice, but it can give information about the number of heartworms present in the pulmonary arteries and the degree of vascular damage and of perfusion in the pulmonary arteries. The technique does take some practice and requires extra effort, but the results can be very useful. The semi-selective technique works better in the smaller dog, preferably less than 15 kg in body weight. Above 15 kg in body weight, the contrast medium becomes too dilute because a large enough volume cannot be injected fast enough. Additionally, the x-ray machine should be capable of generating exposure times of 1160th of a second or less. In larger dogs, a large-bore jugular catheter with the tip placed near the right atrium may be adequate, but selective placement of a cardiac catheter in the pulmonary trunk is ideal. After catheter placement and film exposure confirmation, an ionic or non-ionic contrast medium is used at a dose

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rate of approximately 2.2 mL!kg of body weight (assuming 300 to 400 mg iodine/mL of Hypaque [Sterling Drug, New York, NY] or Omnipaque [Sterling Drug, New York, NY]. Dehyration is a major area of concern when doing an angiogram. When ionic contrast medium such as Hypaque is used, dehydration is exacerbated. In addition, many of the ionic contrast agents have a high sodium content, so caution must be used in the dehydrated patient or the patient with impending cardiac failure . Echocardiography is considered the last diagnostic tool because of the relative sparsity of echocardiography machines in private practice. Echocardiography can, however, be the most reliable diagnostic tool, because the heartworms can be seen directly. The major limitation in echocardiography is that the heartworms must be in the proximal pulmonary trunk, right ventricle, right atrium, or the cranial or caudal vena cava. The heartworms can be seen through normal cardiac imaging sites. The heartworms appear as two parallel white lines of variable length, depending upon the plane of the transducer. The white lines represent the echoic cuticle with the relatively anechoic coelomic space. Additionally, an abdominal echocardiography should be performed, because heartworms have been seen in the abdominal portions of the caudal vena cava. Echocardiography is the method of choice if caval syndrome is suspected. It helps not only in the diagnosis of heartworm disease but also in the treatment via a mechanical device for removal of heartworms through a jugular vein incision. Nuclear imaging is an experimental tool that holds unique potential. Drugs or monoclonal antibodies are labeled with a radioactive isotope, and the combination can be selectively absorbed or metabolized by the heartworm. Such techniques are difficult to perform and require nuclear scintigraphy equipment, but as a specific diagnostic tool to determine the presence or absence of live heartworms, the possibilities are intriguing. The previously mentioned diagnostic methods are presented in somewhat the same order in which most veterinarians would approach the diagnosis of canine heartworm disease. In the cat, the order of diagnostic methods and significance must be reordered. As already mentioned, it is unlikely that a cat will have microfilaria checks as part of annual preventive health maintenance program. The more likely scenario is the clinical presentation of a sick cat. Dillon1 states that a cat with chronic emesis that lives in a heartworm endemic area should have heartworm disease in the differential diagnosis. If, after a physical examination is done and the clinical signs indicate that heartworm disease is a serious consideration, a different diagnostic route should be taken from that taken for the dog. In most instances, thoracic radiography in the cat is the most helpful tool. The radiographic signs are different than those in dogs. In cats, the most consistent sign is enlargement of the peripheral pulmonary arteries; of those, the most likely is the right and left caudal lobar arteries.' Pulmonary trunk enlargement, which is diagnostic for the dog, is rarely seen in the cat. Right ventricular enlargement is not as consistent or as prominent in the cat as in the dog. Figures 4 and 5 are ventrodorsal radiographs of typical radiographic findings in cats with heartworm disease. As an extension of the inflammatory disease in the endothelium and muscular layers of the pulmonary arteries, interstitial and alveolar densities may be seen adjacent to the vessels. The pulmonary parenchymal changes may be seen as early as 1 month after vascular enlargement is noticed, and possibly even sooner. Histopathologically, these areas have extensive eosinophil infiltration and a lesser degree of neutrophil infiltration. At times, the pulmonary

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Figure 4. Ventrodorsai radiograph of a cat with cardiomegaly and enlarged caudal lobar pulmonary arteries (arrow). Although the vascular enlargement is characteristic for heart· worm disease, cardiomegaly also could be attributed to cardiomyopathy. Echocardiography is the most reliable method to differentiate between feline heartworm disease and cardiomyopathy.

parenchymal disease may be so severe as to mask the pulmonary arteries. In such cases, a short course of corticosteroids may clear the parenchymal disease sufficiently to allow better evaluation of the pulmonary arteries. A more sensitive diagnostic tool is pulmonary arteriography, but it is more difficult to do than plain film radiography. A recent study indicates that, at least in the acute case, there is vascular compromise present before plain radiographic changes are seen. The angiographic changes may be seen as early as 75 to 90 days after inoculation, which is approximately 1 month before changes may be seen radiographically.6 Dillon2 found no vascular compromise at the end of a 3-year-study; therefore, there must eventually be a revascularization. Figures 6 and 7 show the results of digital subtraction pulmonary arteriograms at various times after the inoculation of infective larvae. Figure 8 is a scanning electron micrograph showing the lesions produced by heartworms in lobar pulmonary arteries. When the LS larvae enter the cardiovascular system, they are passively swept to the most distal branches of the pulmonary arteries. It is there that the initial immune-inflammatory response occurs. As

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Figure 5. Ventrodorsal radiograph of a cat with enlarged lobar pulmonary arteries (arrow).

There is no noticeable cardiomegaly. The degree of interstitial and alveolar lung disease is dependent upon the stage of heartworm infection and concurrent pulmonary disease. the vascular response progresses, larger vessels become involved until the lobar arteries are compromised. The degree of vascular damage is much greater proportionately than the number of heartworms present. Even fragments of heartworms that have lodged in the distal branches of the pulmonary arteries cause vascular reactions beyond the area of direct contact. Therefore, either the heartWorrns produce factors that cause endothelial and muscular hyperplasia, or the heartworms induce changes that then become self-perpetuating. These extreme changes in the acute stage would account for the acute clinical signs noted on presentation. As in the dog, echocardiography is the most diagnostic tool available if the heartworms are in the right ventricle, proximal pulmonary trunk, or caudal vena cava. Under most conditions, however, heartworms are in the lobar pulmonary arteries and out of reach of the echocardiographic transducer and its restricted window. A problem with echocardiography in the cat is thoracic conformation and pericardia! fat. In thin cats, the pulmonary interlobar window can become quite narrow, making the heart difficult to image. Pericardia! fat degrades the image, but probably not enough to be of concern. However, pericardia) and body fat might change the conformation of the cat enough to make imaging difficult. Tranquilization, light anesthesia, different positioning, and persistence will overcome most of these obstacles. Only about one third of the cats exhibit an eosinophilia or mild anemia. The eosinophilia may be stage-specific and may be confused with that caused

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Figure 6. Dorsoventral digital subtraction angiogram of a normal cat to show the normal distribution of lobar pulmonary arteries (arrow, right caudal lobar artery).

by other parasitic migrations, such as Aelurostrongylus abstrusus or roundworms and bronchial asthma. Donahoe3 reports that the most consistent time of eosinophilia is from 4 to 7 months after inoculation but that an eosinophilia is, at best, sporadic after that time. The presence of a basophilia may be more indicative of heartworm infection. Other changes in the clinical laboratory values are inconsistent and may not be specific for heartworm disease. Microfilaremia, a basis of diagnosis in the dog, is present in cats only 20% of the time. Considering that cats easily could have a unisex infection or low numbers of heartworms present, a low microfilaremia is expected. There is little information on the method and rate of microfilarial clearance as part of the natural body defenses in the cat. To increase the odds of finding microfilaria, a volume larger than the traditional 1 mL of blood should be considered; 2 or 3 mL can be used as an alternative. A direct smear of a small volume of blood is, almost assuredly, a futile procedure. Antigen serologic tests have the same limitations in the cat as in the dog. A major factor is the low numbers of heartworms commonly seen in the cat. Low numbers of heartworms produce a proportionately lower quantity of antigen. First, the heartworms must be of sufficient age to start producing antigens, which are primarily excretory/secretory products produced by female worms. If the infection is less than 6 months old, there is a poor chance that there will be any antigen detection. By the time infections are at least 8 months old, which is when most cat infections become patent, most of the infections

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Figure 7. Dorsoventral digital subtraction angiogram of a cat 210 days after the inoculation of 100 infective larvae of Dirofilaria immitis. At necropsy, there were six adult heartworms in the caudal lobar pulmonary arteries. The damage caused by initial invasion of heartworms into the cardiovascular system is severe, as seen by the extensive lack of perfusion of the caudal portions of the caudal lung lobes. The arrow points to the right caudal lobar artery, where there is an abrupt attenuation of the vessel with only a small portion of patent lumen present. Most of the branches off of the lobar artery are totally occluded.

that can. be detected by the tests will already have been detected by methods such as radiography, clinical signs, and so forth. Transplant studies show that only gravid females secrete or excrete detectable antigen. The sensitivity of the antigen tests ranges from approximately 50% to 80% with one to nine heartworms present. Each test kit has a predetermined sensitivity, which may be altered depending on the technique used to run the test. In one commercial test kit, the incubation time can be increased to increase its sensitivity. Table 1 shows a comparison of data that was presented at the 1992 Heartworm Symposium meeting for different antigen test kits. By the time young heartworms have started producing antigen, much of the damage in the cardiovascular system has occurred.

TREATMENT There are no drugs approved by the Food and Drug Administration to kill or block the development of any stage or form of heartworms in cats. For the

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Figure 8. Scanning electron micrograph of a cat 210 days after the inoculation of 100 infective larvae of Dirofilaria immitis. A normal section of pulmonary artery is seen (N), followed by an abrupt change where there is extensive endothelial proliferation (E). The endothelial proliferation can form cordlike structures that may traverse the lumen of the pulmonary arteries. In some areas, dense, meshlike structures appear to occlude the arterial lumen.

lack of anything better, veterinarians have used thiacetarsamide sodium as an adulticide as they would in dogs. In 1989, the American Heartworm Society made a statemenfb on the recommended procedures for the diagnosis and management of heartworm in cats; they advised to treat a cat as you would a dog; that is, 2.2 mg!kg of body weight of thiacetarsamide sodium twice a day for 2 days. The decision to treat a cat for heartworm disease can be much more difficult than the dog. Even when a definitive diagnosis is made, the effect of the heartworms on the cardiopulmonary system of the cat must be weighed heavily against the possibility of an adverse reaction to thiacetarsamide sodium. Because heartworms do not live as long in the cat and are usually in low numbers, many veterinarians will not treat with thiacetarsamide sodium because of possible complications. In this case, supportive treatment such as corticosteroids should be given until clinical signs resolve. Thiacetarsamide sodium efficacy in the dog is highly variable, and scattered reports of trials in the cat indicate that the efficacy may be even poorer. The range of efficacy in the dog may be from 0% to 100%, with 60 to 70% efficacy a realistic average. Pharmacokinetic studies of thiacetarsamide sodium in the Table 1. PERCENTAGE OF HEARTWORMS DETECTED BY COMMERCIAL ANTIGEN TEST KITS #of Worms

Assure/CH

Assure/CH*

DlroCHEK

CITE

1-4 1-9

64.7% 70.8%

70.6% 79.2%

70.6% 79.2%

58.3%

52.9%

*Initial (conjugate) incubation increased from 5 to 10 minutes. Assure/CH, Synbiotics Corp, San Diego, CA; DiroCHEK; CITE, Synbiotics, San Diego, CA

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dogs and cat9 show that the rate of metabolism is significantly different between the dog and cat. The rate of clearance of the arsenical in the dog is approximately 60 mL!kglmin, whereas the rate in the cat is approximately 40 mL!kg/min. This indicates that cats may clear thiacetarsamide sodium faster than the dog, which gives less exposure time of the heartworms to the drug and thus a lower efficacy. This hypothesis is yet to be definitively proven. Nevertheless, there is no evidence to show that thiacetarsamide sodium is any more efficacious in the cat than in the dog. Adjunctive therapy with corticosteroids and aspirin has helped with some of the complications of thiacetarsamide sodium treatment in the dog. Studies8 in the cat show that aspirin treatment is probably of no benefit, even though the cat can tolerate low doses of aspirin. Low-dose corticosteroid therapy helps clear pneumonitis and vasculitis and makes the cat feel better. Also, clearing the lung fields may assist in the radiographic diagnosis of feline heartworm disease, because the pulmonary arteries can be seen. The only alternative to thiacetarsamide sodium for the treatment of adult heartworms is an experimental drug, melarsamine (RM340, Immiticide [RhoneMerieux, Inc, Athens, GA]). At this time, the manufacturer is seeking Food and Drug Administration approval for the treatment in dogs but not for cats. The drug is probably more efficacious than thiacetarsamide sodium in cats and has the major advantage of being given intramuscularly one time a day for 2 consecutive days. The chemical structure is similar to thiacetarsamide sodium and is classified as a melaminyl thioarsenite. The slight change in chemical structure from thiacetarsamide sodium results in a different degree of red blood cell binding and in serum levels. At this date, few cats have been treated with RM340, but the results of its use in the dog and the few treated cats lead to hope that it will be more efficacious and safer than thiacetarsamide sodium. As with the adulticide, there is no approved microfilaricide for dogs and cats. Anecdotal experience has shown that ivermectin is as efficacious in the cat as in the dog. Again, judgment must be used. If a cat has a low microfilaremia, as occurs most commonly, a microfilaricidal dose of ivermectin might not be used in favor of a natural clearing of microfilaria. PREVENTION

Prevention of feline heartworm disease is another topic that is gammg more attention. The incidence of heartworms in cats may be as high as 15% in endemic areas, and the fact that heartworm disease can be lethal for the cat should be a cause for concern. Again, the lack of scientific information for the cat forces the veterinarian to rely on dog information. The limited amount of information available on heartworm prevention suggests that diethylcarbamazine, ivermectin, or milbemycin is well-tolerated by the cat and appears to be efficacious. The natural nocturnal habits of the cat coincide with the nocturnal habits of mosquitoes. It would appear, therefore, that cats that are outside, especially in the evening or all night, are at risk of becoming infected with heartworms. It would therefore seem prudent for the veterinarian to be aware of the risk of heartworm infection in a community and offer some form of prevention to the client. SUMMARY

The cat must be recognized as a different entity than a dog when considering heartworm disease. The cat responds differently than the dog to

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larval migration, adult development, and therapy. As a result of these differences, the clinical signs shown by the cat and the therapeutic alternatives must be considered as unique to the cat. The diagnosis of heartworm disease in cats usually is more difficult than in the dog; therefore, the veterinarian must be more aware of the strengths and weaknesses of thoracic radiography, microfilaremia tests, and serologic tests than in the dog. Clinical signs in the cat are usually more vague and generalized than in the dog. When a diagnosis of heartworm disease in cats is made, the decision of which therapeutic regimen to use is a challenge. In many instances, the best treatment (except for supportive treatment) may be no treatment. Knowledge of the incidence of heartworm disease in an area may determine whether a veterinarian counsels a client to consider one of the preventive medications. References 1. Dillon AR: Feline heartworm disease. In Proceedings of the Heartworm Symposium 1986. Washington, DC, American Heartworm Society, 1986, pp 149-154 2. Dillon AR, Brawner WR, Grieve RB, et a!: The chronic effects of experimental Dirofilaria immitis infection in cats. Semin Vet Med Surg (Small Animal) 2:72-77, 1987 3. Donahoe JMR: Experimental infection of cats with Dirofilaria immitis. Parasitol61 :599605, 1975 4. Donahoe JMR, Kneller SK, Lewis RE: Hematologic and radiographic changes in cats after inoculation with infective larvae of D immitis. JAm Vet Med Assoc 168:413-417, 1976 5. Holmes RA, McCall JW, Prasse KW, eta!: Thiacetarsamide sodium: Pharmacokinetics and the effects of decreased liver function on efficacy against Dirofilaria immitis in dogs. In Proceedings of the Heartworm Symposium 1986. Washington, DC, American Heartworm Society, 1986, pp 57-64 6. Holmes RA, Clark JN, Casey HW, et a!: Histopathologic and radiographic studies of the temporal development of heartworm pulmonary vascular disease in experimentally infected cats. (Abstract). In Proceedings of the Heartworm Symposium 1992. Washington, DC, American Heartworm Society, 1992, in press 7. Lewis RE: Radiographic findings in feline dirofilariasis. In Proceedings of the Heartworm Symposium 1986. Washington, DC, American Heartworm Society, 1986, pp 155-158 7a. McTier TL, McCall JW, Dzimianski MT, eta!: Epidemiology of heartworm infection studied by using naturally exposed "tracer" beagles in three southeastern states (USA). In Proceedings of the Heartworm Symposium 1992. Washington, DC, American Heartworm Society, 1992, in press 7b. Otto GF (ed): Recommended procedures for the diagnosis and management of heartworm (Dirofilaria immitis) infection. In Proceedings of the Heartworm Symposium 1989. Washington, DC, American Heartworm Society, 1989, p 231 8. Rawlings CA, Mahood RM, Farrell RL, et a!: Feline heartworm disease: Effect of aspirin. In Proceedings of the Heartworm Symposium 1989. Washington, DC, American Heartworm Society, 1989, pp 59-65 9. Turner JL, Lees GE, Brown SA, et a!: Thiacetarsamide in normal cats: Pharmacokinetic, clinical, laboratory and pathologic features. In Proceedings of the Heartworm Symposium 1989. Washington, DC, American Heartworm Society, 1989, pp 135-141

Address reprint requests to Robert A. Holmes, DVM, PhD Department of Veterinary Clinical Sciences Louisiana State University School of Veterinary Medicine South Stadium Drive Baton Rouge, LA, 70803