HEARTWORM DISEASE

Clarke E. Atkins, D.V.M., Diplomate, A.C.V.I.M (Internal Medicine and Cardiology)
William G. Ryan, M.B.A., B.V.Sc.

Infection of a cat with Dirofilaria immitis was first recognized in the United States in 1922. There have been numerous subsequent reports, with a recent review of 156 previously reported cases. Despite this, feline heartworm disease (FHWD) has generally been considered a novelty, with many veterinarians still believing that the cat is not at risk. This is an unfortunate misconception, as not only is the cat susceptible, but also its clinical signs are more severe than those of the dog, even when the worm burden is quite small. In recent years, increasing awareness has brought the development of better diagnostic tests, efforts at establishing a satisfactory adulticidal therapy, increasing public awareness, and, recently, the registration of a feline heartworm preventive.

PREVALENCE IN THE UNITED STATES

Heartworm infection is less com on in cats than in dogs, approximating 5 to 20% of the canine prevalence in a given geographic area. This has led to a low index of suspicion for FHWD, with resultant underdiagnosis. In addition, the diagnosis of FHWD is often obscured because (1) cats are frequently amicrofilaremic; (2) serologic tests (respectively, the enzyme-linked immunosorbent assay [ELISA] antigen and antibody tests) have lacked sensitivity or specificity in cats; (3) worm burdens are small; (4) aberrant sites are more common than in dogs; and (5) clinical signs are often nonspecific and different from those seen in dogs. For these reasons, despite recent efforts at defining the scope of this problem in cats, the exact prevalence of FHWD is unknown and likely underestimated.

A review of studies reporting feline heartworm infection (FHWI) and a survey of veterinary practitioners revealed that the diagnosis has been made in 38 of the 50 United States. Not surprisingly, the greatest numbers of cases have been reported from the southeastern United States, the Eastern Seaboard, and the Gulf Coast and within the Mississippi River valley. Prevalence studies have focused mainly on cats from shelters. While this population choice has allowed the use of the relatively sensitive and very specific postmortem diagnosis, these studies are not necessarily applicable to pet cats, even in the same geographic region. These 12 studies, from 10 southeastern states, have revealed a prevalence of FHWI ranging from 0 to 16%. There are limited data in pet cats, but a joint study, performed on such cats presented to the teaching hospitals of North Carolina State University (NCSU) and Texas A&M University for evaluation of cardiorespiratory signs, demonstrated an infection prevalence of 9% and an exposure rate of 26%, the latter figure based on antibody titers. A number of serologic surveys, largely in asymptomatic cats, have demonstrated exposure rates (antibody seropositivity) of 5 to 36%, even in areas not considered heavily heartworm endemic and as high as 43% in asymptomatic cats.

The diagnosis of FHW1 or FHWD poses a unique and problematic set of issues. First, the clinical signs in cats are often
quite different from those in dogs. Then, the diagnostic effort is often inadequate because the suspected incidence in cats is
low. Furthermore, the diagnosis is often elusive because eosinophilia is transient or absent; electrocardiographic findings are
minimal; and most cats are amicrofilaremic. Radiography, while helpful, is neither adequately sensitive nor specific and
requires expertise in interpretation. Echocardiography shows promise in terms of specificity but is costly and only moderately sensitive, and requires special equipment and expertise. Currently, the most useful tests include ELISA serologic tests. These too are imperfect. The antigen test is very specific but is inadequately sensitive, missing over 50% of natural infections. On the other hand, a recently developed feline antibody test is very sensitive, but its specificity is low, meaning that a positive test indicates -exposure, but not necessarily adult infection.

Heartworm-infected cats may be asymptomatic, and clinical manifestations, when present, may take either an acute (often cataclysmic) or a chronic (often waxing and waning) course. Acute or peracute presentation is usually due to dead worm embolization or migration of worms to the central nervous system, and signs variably include salivation, tachycardia, shock, dyspnea, cough or hemoptysis, vomiting and diarrhea, syncope, dementia, ataxia, circling, head tilt, blindness, seizures, and death. Sudden death, with little or no premonitory signs, has been observed in approximately 23% of cases. Cats that die suddenly may appear clinically normal up to 1 hour before death. Postmortem examination has revealed as few as two worms in cats that have died suddenly. Postmortem examination typically reveals pulmonary infarction with congestion and edema. Vena caval syndrome has also been recognized in cats.

Findings in chronic FHWD may include cough, dyspnea, anorexia, weight loss, lethargy, exercise intolerance, vomiting, and signs of right-heart failure. Cough is a relatively consistent finding (>50% of cases, compared with 15% in cats with cardiorespiratory signs, but not FHWI and, when noted in cats in endemic areas, should increase the suspicion of FHWD. Likewise, dyspnea, though less specific than cough, is present in 40 to 60% of cases. The pulmonary response to in situ heartworms in cats includes type 11 cell hyperplasia and activation of pulmonary intravascular macrophages. This response, not recognized in dogs, may explain the astlima-like syndrome recognized in some cats, even after they have been cleared of D. immitis.

Physical examination is often unrewarding, although a murmur, gallop, and/or diminished or adventitial lung sounds may be noted. In addition, cats may be thin and/or dyspneic. If heart failure is present, jugular venous distention, pleural effusion, and rarely ascites are detected

Microfilarial Tests. A definitive diagnosis of FHWl can be made by the detection of circulating microfilariae, using the modified Knott test, millipore filter, direct smear, or microhematocrit techniques. A recent literature review indicated that 36% of 45 cats with FHWD were microfilaremic, while other reports have indicated no more than 20% of infected cats are microfilaremic. This discrepancy probably reflects the fact that at the time of early reports diagnostic methods were limited to microfilarial tests and postmortem examination. While increasing the volume of blood samples, multiple testing, and drawing evening samples may increase the diagnostic efficiency of the microfilariadependent tests, the low percentage of cats that become microfilaremic, the transient nature of microfilaremia, and the low microfilarial numbers seriously limit their utility.

Antigen Tests. Although virtually 100% specific, ELISA antigen tests have been of somewhat limited use in cats because
of the inability of these tests to detect low worm burdens ><2 worms); in general, infected cats have I to 12 (most often 1, almost always <5) worms. Additionally, current tests detect antigens presumably produced in the reproductive tracts of mature female worms; thus, they do not detect immature (<7 months) or all-male infections. These factors may result in false-negative results, and their importance is underscored by a recent review of 108 naturally occurring cases of FHWD that revealed that 53% harbored single-worm infections and 18% had all-male infections. Furthermore, it is now clear that clinical signs may exist prior to worm maturation, at a time when cats are antigen negative. These limitations are demonstrated in two studies. First, in a study of six commercial ELISA antigen tests, positive test results were obtained, 36 to 93% of the time, from the sera of 31 known positive cats harboring I to 7 female worms. Although sensitivity increased with greater female worm burdens, no all-male heartworm infections were detected. Second, a commercial antigen test allowed detection of fewer than 40% of necropsy-proven natural infections. False-negative antigen test results occur frequently, depending on the test used, the maturity and gender of the worms, and the worm burden. Recent advances in the sensitivity of ELISA antigen tests will probably improve their efficiency in the diagnosis of infections containing at least 1 female worm. Although the specificity of antigen tests is well accepted, the risk of false-positive results increases with low prevalence. Therefore, positive test results should be confirmed by a second test or supported by the presence of appropriate clinical findings (e.g., cough, radiographic lesions, echocardiography).

Antibody Tests. There are now three commercially available, "send-off" ELISA antibody tests, designed specifically for the diagnosis of FHWI (Animal Diagnostics, Inc., St. Louis, MO, HESKA Corporation, Fort Collins, CO, and Antech Diagnostics, Fanningdale, NY) and two ELISA antibody tests (ASSURE/FH, Synbiotics Corp, San Diego, CA, and Solo Step PH, HESKA Corp, Fort Collins, CO) designed for "in-house" use. There is now published documentation only on the "send-off" tests, suggesting higher specificity than has been found with previous antibody tests. Although less specific than the antigen tests, the commercial ELISA antibody test is capable of detecting male-only and immature infections and has been shown to be useful in the detection of FHWI even when antigen test results are negative. The antibody tests were shown to be 100% specific in determining cats to be heartworm negative prior to infection and detected 80% of experimental infections by 2 months, 97 to 100% by 3 months, and 100% by 4 months after infection (McCall et al, 1998). The antibody test was used to screen 215 random-source cats and detected 7 of 8 necropsy-proven cases (sensitivity = 88%) but at the same time gave "false-positive" results for 21 cats (90% specificity). The strength of this test is in ruling out infection (>99% negative predictive value), but a positive test clearly does not always indicate mature or current infection (positive predictive value = 25%). A negative antibody test indicates either no infection or an early (<50- to 60day) infection. A positive test result is thought to mean that (1) adults are present in the heart and/or pulmonary arteries, (2) past resolved infection with antibodies is still present, (3) precardiac late larva 4 (L4) or immature L5 infection exists, or (4) ectopic infection is present. Ideally, a positive test result should be confirmed with an antigen test, echocardiograpby, or angiography and supported by the presence of appropriate clinical findings (e.g., cough, radiographic lesions). In addition to aiding in making a diagnosis of FHWL the antibody test may be useful as a marker for exposure to heartworms, even in cats that never develop mature infection. Finally, the antibody test is currently the most logical screening test for asymptomatic cats.

Radiography. Radiographic findings of FHWD include enlarged caudal pulmonary arteries, often with ill-defined margins; pulmonary parenchymal changes, including focal or diffuse infiltrates (interstitial, bronchointerstitial, or even alveolar); perivascular density; and, occasionally, atelectasis or pleural effusion. Pulmonary hyperinflation and right-heart enlargement may also be evident. Thoracic radiography has been suggested as an excellent screening test for FHWD. However, while often helpful, thoracic radiography is neither sensitive nor specific in making the diagnosis of FHWD. The single most sensitive radiographic criterion (left caudal pulmonary artery diameter greater than 1.6 times that of the ninth rib at the ninth intercostal space) can be identified in only 53% of cases and may also be noted in cats with heart failure, but not FHWI. Likewise, pulmonary parenchymal changes are only detectable radiographically in approximately 50% of natural cases. Even though most cats with clinical signs have some radiographic abnormality, the findings are not specific for FHWD, are variable, and are often transient. Lastly, radiographic abnormalities have been detected in experimentally exposed cats that ultimately resisted heartworm maturation and were negative on postmortem examination (i.e., false-positive). On the other hand, pulmonary angiography can be used to make a definitive diagnosis by the demonstration of radiolucent intravascular "foreign bodies," as well as enlarged, tortuous, and blunted pulmonary arteries.

A,Thoracic radiograph from a cat with mild radiographic signs of heartworm disease. Note the right caudal pulmonary artery (arrow). The arrow is located in the ninth intercostal space, the site for comparison of the ninth rib with the pulmonary artery (right or left side). If the pulmonary artery is greater than 1.6 times the size of the rib, it is suggestive of heartworm disease (Schafer and Berry, 1995). B, Thoracic radiograph obtained from a more severely affected cat. Note the alveolar infiltrate in the caudal lung lobes. (From Schafer M, Berry CR: Cardiac and pulmonary artery mensuration in feline heartworm disease. Vet Radiol Ultrasound 36:499, 1995.)

Echocardiography. Echocardiography is more sensitive in cats than in dogs for the detection of heartworm infection. Typically, a "double-lined echodensity" (Fig. 4) is evident in the main pulmonary artery, one of its branches, or the right ventricle, or occasionally at the right atrioventricular junction. FHWI was detected echocardiographically in 7 of 9 natural cases and 12 of 16 experimental infections. A retrospective review of a larger case series revealed a lower sensitivity when worms were not specifically sought and, particularly, when studies were performed by noncardiologists. This observation underscores the need for a high index of suspicion and expertise if this technique is to be of value in the diagnosis of FHWI.

A two-dimensional echocardiogram
    obtained from a cat with heartworm disease.

   A double-lined density
    (adult heartworm, indicated by arrow)
    is evident and is diagnostic for heartworm
infection.

Ao, aorta; RV, right ventricle; LA, left atrium.

Ivermectin, administered as a single dose of 24 jig/kg, and milbernycin oxime, administered at 500 mcg/kg in two doses 1 month apart, effectively prevent FHWI when exposure has occurred during the previous month. In late 1996, the FDA approved ivermectin as a feline heartworm preventive for administration in a chewable formulation (Heartgard for Cats, Merial, Iselin, NJ). Ivermectin has been demonstrated to have an excellent safety profile, with no adverse effects in kittens at doses exceeding 110 mcg/kg and doses of at least 750 mcg/kg in adults. Although not marketed for cats, milbernycin has recently received FDA approval as a feline heartworm preventive at a dosage of 2000 mcg/kg.

Based on disease severity, the lack of an effective and safe adulticidal therapy, and the difficulty in making a definitive diagnosis, the authors believe that cat owners in endemic areas should be offered the choice of their pet receiving a heartworm preventive. Clearly, cats already infected with heartworms and their house mates should be placed on a
preventive.