Heartworm Disease in Dogs, Cats, and Ferrets

The role of the endosymbiotic bacteria Wolbachia pipiens, which live intracellularly within the filarid parasite, is still being determined. However, these bacteria have been implicated in the pathogenesis of filarial diseases, possibly through endotoxin production. Furthermore, studies have demonstrated that a primary surface protein of Wolbachia (WSP) induces a specific IgG response in hosts infected by D immitis. For veterinarians, the most important aspect of Wolbachia is its symbiotic relation with D immitis. This bacterium is necessary for normal maturation, reproduction, and infectivity of the heartworm. If Wolbachia are eradicated, the heartworm gradually dies, after first becoming sterile. This can be accomplished with doxycycline therapy, which has become an important part of the armamentarium against heartworms.

Infected cats may be asymptomatic or exhibit intermittent coughing, dyspnea, heart failure, vomiting, lethargy, anorexia, or weight loss See table: Diagnostic Tests, Clinical Signs, and Treatment for Heartworms in Dogs, Cats, and Ferrets Diagnostic Tests, Clinical Signs, and Treatment for Heartworms in Dogs, Cats, and Ferrets . When evident, signs usually develop during two phases of the HW life cycle: 1) the arrival of juvenile worms in the pulmonary vasculature ~3–4 months after infection, and 2) death of adult heartworms. The early signs are associated with an acute vascular and parenchymal inflammatory response to the newly arriving young worms and the subsequent death of many or all of these juveniles. This initial phase is often misdiagnosed as asthma or allergic bronchitis. However, this is now considered to be HARD; for this discussion, the term HARD refers to signs of immature HW infection, whereas HWD in cats refers to mature infection. Antigen tests in such cats are negative (measured antigens are associated with mature female worms) during the early eosinophilic pneumonitis syndrome, although antibody tests typically are positive. Although not yet well characterized, it is believed that clinical signs often resolve and may not reappear or may be silent for months. HARD has been postulated to contribute to longterm lung damage, but proof is lacking. Cats harboring mature worms (HWD) may exhibit intermittent vomiting, lethargy, coughing, episodic dyspnea, and CHF, manifested by pleural effusion. Death of even one adult heartworm can lead to acute respiratory distress and shock, which may be acutely fatal and appears to be the consequence of pulmonary thrombosis and/or anaphylactic-like shock.

Ferrets, more so than cats, mimic canine HW infection in terms of clinical signs. The large parasite:host body weight ratio dictates that ferrets (and cats) develop clinical signs with relatively small worm burdens. Ferrets with HW disease may demonstrate one or more of the following:

See table: Diagnostic Tests, Clinical Signs, and Treatment for Heartworms in Dogs, Cats, and Ferrets Diagnostic Tests, Clinical Signs, and Treatment for Heartworms in Dogs, Cats, and Ferrets

The antigen detection test is the preferred diagnostic method for routine screening or when seeking verification of a suspected HW infection. Antigen testing is the most sensitive and specific diagnostic method available to veterinary practitioners. Microfilaria testing is limited by the fact that ~20% of infected dogs are amicrofilaremic. This percentage is even higher for dogs infected with adult heartworms and that are consistently administered monthly macrolide prophylaxis, because this kills microfilariae and induces embryostasis in mature female dirofilariae.

Timing of antigen testing is critical. A predetection period must be considered, because these tests detect only adult, female worms. This takes into account the time from exposure to seroconversion (ie, positive antigen test result). A reasonable interval is 7 months after last possible exposure. There is no value in testing a dog for antigen or microfilariae before ~7 months of age. To ensure that a previously acquired infection does not exist in these young dogs, they should be tested 6–7 months after beginning HW prophylaxis. For dogs >7 months old at first presentation and not on HW prophylaxis, testing should be performed at that time and 7–12 months after initiating preventive therapy. Subsequently, annual antigen detection tests are recommended.

The terminology for HW antigen tests is changing, with some experts replacing the word "negative" 'with “below detectable limits” to underscore the possibility that HW-infected pets with a negative test may convert to positive as worms mature or that small-burden female infections may test inappropriately negative.

The level of antigenemia is directly related to the number of mature female worms present. Most dogs harboring more than two adult female worms will test positive with most available tests. For low-burden suspects, commercial laboratory-based microwell titer tests are the most sensitive. There is, however, no test that can accurately determine worm burden. Testing for microfilariae may be useful as an adjunctive test in suspect cases that have negative antigen test results. In addition, antigen-testing heat-treated serum can change a false-negative to a positive result. Heating breaks down complexes of the antigen being tested for and antibodies (blocking antibodies) formed against the parasite antigens. This frees antigen, making it detectable.

Microfilaria testing is no longer the primary means of testing for HW. Nevertheless, it has value because a small percentage of HW-infected dogs are antigen-negative and microfilaria-positive, allowing an otherwise missed diagnosis to be made. It is of extreme importance to check for microfilariae when there is a positive antigen test, due to the need to understand microfilarial burden and hence risk of reaction to first macrocyclic lactone administration and so that, if present, microfilariae can be eliminated so that risk of resistance development is not impacted during therapy with macrocyclic lactones.

In dogs, echocardiography is relatively unimportant as a diagnostic tool, although it can allow assessment of cardiac damage and performance. Visualization of worms in the right heart and vena cava is associated with high-burden infection with or without caval syndrome. Severe, chronic pulmonary hypertension causes right ventricular hypertrophy, septal flattening, underloading of the left heart, and high-velocity tricuspid and pulmonic regurgitation. The ECG of infected dogs is usually normal. However, right ventricular hypertrophy patterns are seen when there is severe, chronic pulmonary hypertension, often associated with overt or impending right-side CHF (ascites). Cardiac rhythm disturbances are usually absent or mild, but atrial fibrillation is an occasional serious complication in dogs.

The diagnosis of HW infection in cats is based on historical and physical findings, index of suspicion, thoracic radiographs, echocardiography, and serologic test results. Cats may develop a positive antigen test 7–8 months after L₃ inoculation. However, antigen tests alone are considered too unreliable (insensitive, missing 25%–50% of mature infections) as the initial screening test for cats. This occurs with unisex (all male) infections, infections with insufficient numbers of mature females to be detectable, and in cats with HARD. Cats with HARD remain antigen negative, if no adult worms develop. Cats with mature infections are also occasionally found to be temporarily negative, if tested before detectable antigenemia develops. Nevertheless, the antigen test is strongly recommended in cats in which HW infection is suspected.

Antibodies to heartworms, produced by 90% of infected cats, often appear by 2–3 months after L₃ infection and are generally present by 5 months. However, antibodies can persist for several months after worm death. Also, antibodies induced by larvae can persist in aborted infections and after macrolide prophylaxis has been instituted, killing the early larval stages. Thus, a positive antibody test indicates infection by HW larval stages, and possibly HARD, but not necessarily of a mature infection. In conjunction with other provocative findings, antibody seropositivity is useful in making a clinical diagnosis of HW infection in cats, and it certainly identifies cats at risk. False-positive results from cross-reactivity with other parasites have not been seen. A negative antibody test indicates ≥90% probability of the absence of mature infection. Microfilariae are rarely detected (< 10%) in cats, regardless of method of detection. Annual screening of cats is not necessary but may yield information for concerned cat owners. For this purpose, the antibody test is preferred in that it detects cats with heartworms and those at risk. The antigen test is not appropriate for screening in cats because of its low sensitivity.

In cats, worms can often be imaged using echocardiography. This is because of the relative sizes of the heartworm(s) and the right heart and pulmonary arterial system of cats. Heartworms, particularly the females, are long enough to occupy the pulmonary arteries as well as the right heart, where they can be easily imaged. Parallel hyperechoic lines, produced by the HW cuticle, may be seen in the right heart and pulmonary arteries. Echocardiography is more important in cats than in dogs because of the increased difficulty of diagnosis in cats (low antigen test sensitivity and low antibody test specificity for mature infection) and the relatively high sensitivity of the test in experienced hands.

In ferrets, commercial antigen tests have detected HW antigen in experimental infection as early as 5 months after infection and are effective in clinical situations. False-negative results may occur, especially in species that harbor lower worm burdens (cats and ferrets). Furthermore, although microfilaria testing is only rarely helpful, adult worms can often be seen with echocardiography and nonselective angiography.

In addition to antigen, antibody, and microfilaria tests in cats and dogs, a CBC, chemistry profile, urinalysis, and particularly, thoracic radiographs are sometimes indicated. Laboratory data are often normal. Eosinophilia and basophilia alone or together may occur in dirofilariasis. Eosinophilia is most often seen at the time that stage 5 (young adult) larvae arrive in the pulmonary arteries. Subsequently, eosinophil counts vary but are usually high in dogs with immune-mediated occult infections, especially if eosinophilic pneumonitis develops (< 10% of total infections). Anemia in HW-infected dogs occurs due to chronic inflammation (usually mild) and due to hemolysis (more severe) seen with the complications of DIC and caval syndrome.

Hyperglobulinemia, due to antigenic stimulation, may be present in dogs and cats. Hypoalbuminemia in dogs can be associated with proteinuria in severe immune-complex glomerulonephritis or with severe emaciation/cardiac cachexia. Serum ALT and alkaline phosphatase are occasionally increased but do not correlate well with abnormal liver function, efficacy of adulticide treatment, or risk of drug toxicity. Urinalysis may reveal proteinuria that can be quantitated by a urine protein:creatinine ratio. Occasionally, severe glomerulonephritis can lead to hypoalbuminemia and nephrotic syndrome. Dogs with hypoalbuminemia, secondary to glomerular disease, also lose antithrombin III and are at risk of thromboembolic disease. Hemoglobinuria is associated with caval syndrome and occurs when RBCs are lysed in the circulation.

In dogs, thoracic radiography provides the most information on disease severity and is particularly important in patients with clinical signs. High-risk infections are characterized by a large main pulmonary artery segment and dilated, tortuous caudal lobar pulmonary arteries. Right ventricular enlargement may also be seen and, along with enlarged pulmonary arteries, is indicative of pulmonary hypertension. With pulmonary thromboembolism and pulmonary infiltrate with eosinophils (pneumonitis), ill-defined parenchymal infiltrates surround the caudal lobar arteries, typically most severe in the right caudal lobe.

In cats, cardiac changes and pulmonary hypertension are less common. In ~50% of infected cats, caudal lobar arteries are larger than the corresponding vein and >1.6 times the diameter of the ninth rib at the ninth intercostal space. Patchy parenchymal infiltrates may also be present in cats with respiratory signs. The main pulmonary artery segment usually is not visible because of its relatively midline location.

In ferrets, radiographs can demonstrate cardiac and pulmonary arterial changes compatible with HW disease. In addition, adult worms can often be seen with echocardiography and nonselective angiography.

The extent of the preadulticide evaluation varies, depending on the clinical status of the dog, the likelihood of coexisting diseases that may affect the outcome of treatment, the owner's ability to restrict the dog's exercise, and cost considerations. Clinical laboratory data should be collected selectively to complement information obtained from a thorough history, physical examination, antigen and microfilaria tests, and often, thoracic radiography.

Two important variables known to directly influence the probability of posttreatment thromboembolic complications and treatment outcome are the extent of concurrent pulmonary vascular disease and the current worm burden. Assessment of cardiopulmonary status is indispensable for evaluating a dog's prognosis. Pulmonary thromboembolic complications after adulticide treatment are most likely to occur in heavily infected dogs already exhibiting clinical and radiographic signs of severe pulmonary vascular disease, especially when severe pulmonary hypertension and CHF are present. There is currently no effective way to determine worm burden other than direct visualization echocardiographically. Most cases do not warrant this test.

Before adulticide therapy, HW-infected dogs are assessed and rated for risk of postadulticide thromboembolism. Dogs can be categorized as follows:

Dogs in the low-risk category would ideally fulfill the following conditions: young, with no clinical signs, normal thoracic radiographs, a low level of circulating antigen or a negative antigen test with circulating microfilariae, no worms visualized by echocardiography, no concurrent disease, and with owners capable of completely restricting exercise. The low-risk group would also include dogs having previously undergone adulticidal therapy but that remain antigen positive (presumed low worm burden). Dogs with near-normal thoracic radiographs may develop severe thromboembolic disease, occurring most often when exercise is not restricted. Dogs at high risk of thromboembolic complications include those with signs related to HW infection (eg, coughing, dyspnea, ascites), abnormal thoracic radiographs, high level of circulating antigen, worms visualized by echocardiography, concurrent disease, and little or no possibility that the owners will restrict exercise.

After evaluation, risk assessment, and financial consideration, an adulticidal treatment is chosen. These approaches ( see Table: Guide to Choosing Heartworm Therapeutic Protocol Guide to Choosing Heartworm Therapeutic Protocol ), listed in order of highest to lowest, regarding safety, efficacy, duration of therapy, and cost, include:

High-risk dogs should be stabilized before melarsomine administration. Adulticidal therapy often precipitates worsening of pulmonary and/or cardiac signs as worms die. Stabilizing treatment includes cage confinement, oxygen, corticosteroids, and doxycycline for 1–2 months before initiation of the split-dose melarsomine treatment protocol. The use of doxycycline and the split-dose protocol lessens the adverse reaction to dying worms.

Dogs with right-side CHF should be treated with:

Sildenafil can be used initially at 1 mg/kg, three times daily, as a pulmonary vasodilator. Caution is warranted with this and other vasodilators to avoid the adverse effect of systemic hypotension. Adulticidal therapy should be delayed indefinitely in dogs with CHF.

Caval syndrome results from worms migrating retrograde to the right atrium and great veins and is usually the result of a precipitous fall in cardiac output, as might occur with pulmonary thrombosis. Severe pulmonary hypertension is then complicated by worm-induced tricuspid valve leakage, hemolysis, and damage to the liver and kidneys.

In caval syndrome, removal of worms from the right atrium and orifice of the tricuspid valve is typically necessary to save the life of the dog. This may be accomplished by using light sedation, local anesthesia, and either rigid or flexible alligator forceps or an intravascular retrieval snare, introduced preferentially via the right external jugular vein. With fluoroscopic guidance, if available, the instrument should continue to be passed until worms can no longer be retrieved. Immediately after a successful operation, the clinical signs should lessen or disappear. Fluid therapy may be necessary in critically ill, hypovolemic dogs to restore hemodynamic and renal function. After full recovery from surgery, adulticidal therapy is undertaken to eliminate remaining worms. Particular care should be taken if many worms are still visible echocardiographically.

The only approved heartworm adulticide is melarsomine dihydrochloride, which is variably effective against mature (adult) and immature heartworms of both sexes, with male worms being more susceptible. Melarsomine is given at 2.5 mg/kg, deep IM in the belly of the epaxial (lumbar) musculature in the area of the third to fifth lumbar vertebrae, using a 23-gauge needle (1 in. long for dogs < 10 kg or 1.5 in. for dogs >10 kg). Pressure at the injection site is applied and maintained for 5 minutes to prevent drug migration.

Approximately one-third of dogs will exhibit local pain, swelling, soreness with movement, or rarely, sterile abscessation at the injection site. Local fibrosis is not uncommon (and is the reason for targeting the belly of the epaxial musculature). In standard use, the procedure is repeated on the opposite side 24 hours later for dogs at low risk of treatment complications. However, to reduce the danger of thromboembolism, a two-phase (also termed “split-dose” or "three-dose” method) treatment is highly recommended for at-risk dogs and, indeed, for all patients, unless cost considerations prohibit this approach. Using this protocol, a single injection of melarsomine is given, followed by two injections 24 hours apart, after an interval of at least 30 days. The American Heartworm Society recommends this three-dose alternative regimen, regardless of the stage of disease or risk category.

Exercise restriction is essential once treatment is started to minimize the risk of pulmonary thromboembolism due to dead and dying adult worms. Further benefits accrue with the addition of doxycycline therapy.

The current ideal approach to adulticidal therapy is to give doxycycline (10 mg/kg, twice daily, for 30 days; reduced to 5 mg/kg if not tolerated) and HW preventive, at the standard preventive dosage and frequency (monthly or every 6 months). After 2 months, adulticidal injections (melarsomine at 2.5 mg/kg, IM) are initiated as the dog's condition allows. Daily corticosteroids, using a tapering dosage, may also be administered during this period to reduce pulmonary inflammatory lesions from dying worms and from melarsomine. Although exercise is minimized from the day of diagnosis, cage rest must be enforced from the day of each initial injection for 4–6 weeks. If the dog's condition allows, melarsomine injections are repeated in 1 month (2 injections 24 hours apart), with the same regimen of prescribed exercise restriction. If, after the first injection, the dog displays significant pulmonary damage from the resultant worm death, the second and third injections can be withheld indefinitely.

Dogs with high worm burdens are at risk of severe respiratory complications. Because only ~50% of heartworms are destroyed after the first injection and because worm antigenic burden has been reduced by the wolbachiostat, doxycycline, the cumulative impact of worm emboli on severely diseased pulmonary arteries and lungs is reduced. This approach destroys a higher percentage of adult heartworms than the standard two-dose protocol. For the utility and advisability of various therapeutic protocols, see Table: Guide to Choosing Heartworm Therapeutic Protocol Guide to Choosing Heartworm Therapeutic Protocol .

Doxycycline has become an important part of treatment of HW infection in dogs. Through its negative action on Wolbachia, it provides benefits to the canid host and works to the detriment of D immitis. Doxycycline is indicated for preadulticide therapy (at 10 mg/kg, twice daily, for 30 days, or 5 mg/kg, twice daily, if not tolerated) in HW-infected dogs. It is given in conjunction with ivermectin at the preventive dosage (6–12 mcg/kg/month). This combination reduces the severity of lung injury after adulticidal therapy, probably through reducing the amount of Wolbachia antigen and the proteins released from the HW uterus as the bacteria die and the uterus degenerates. Doxycycline at this dosage hastens worm death when a “slow-kill” approach is used, thereby presumably reducing the negative impact of worms on the host. Doxycycline with a macrocyclic lactone also clears the host of microfilariae (in both resistant and nonresistant infections). Therefore, in dogs undergoing slow-kill treatment, this combination decreases risk of macrolide resistance, which is a concern in the slow-kill method using ivermectin alone. Doxycycline is advocated in treating dogs with HW infection regardless of severity classification or protocol.

The American Heartworm Society recommends administration of prophylactic doses of macrolides for 2 months before administration of melarsomine, with the first dose given concurrently with the first dose of doxycycline (day 1) and a second dose given after the end of the doxycycline treatment (day 30). A third dose is then given concurrently with the first dose of melarsomine (day 60). Macrolide administration is continued monthly thereafter at the preventive dosage. The rationale for this approach is to eliminate susceptible migrating D immitis larvae and to allow nonsusceptible 2–4 month old larvae to age to a point at which they are more susceptible to melarsomine. This approach of a 2-month pretreatment with macrolides has become less compelling with the recent knowledge that doxycycline kills developing larvae (L₃>L₄>young adults) when administered at 10 mg/kg, twice daily, for 30 days, thereby closing the gap during which developing larvae are not susceptible to melarsomine treatment. However, the delayed institution of melarsomine for 2 months still makes sense. Though unproven, the degeneration of the HW, which starts at inception of doxycycline therapy, is likely not maximized at one month but is more advanced with another 30 days' time for worm degradation. This should further reduce the reaction of the host to dying parasites.

Cases in which non-arsenical adulticidal therapy might be considered:

Although generally agreed that the only FDA-approved approach and the American Heartworm Society's recommendation for treating HW is ideal, financial and other concerns, as well as melarsomine availability, dictate the need for alternatives. Most have focused on the use of macrocyclic lactones in a "slow-kill" or "soft-kill" approach. This is controversial, largely because of the duration of therapy, reliance on patient compliance for years, ongoing host damage, and concern for resistance development. More recently, the addition of doxycycline has been shown to reduce the duration of therapy necessary for an ~95+% kill rate from ~2.5 to ~1 year. Furthermore, the combination of doxycycline plus moxidectin/imidacloprid at preventive dosage, given biweekly for the first 6 months, resulted in 96% HW-antigen negative status in an average of ~8 months. Ivermectin and doxycycline, used similarly, provided 78% negative tests at 300 days. This rate of HW antigen clearance is approximately that of the split-dose melarsomine protocol.

After melarsomine injection(s), exercise must be restricted for 4–6 weeks to minimize pulmonary thromboembolic complications. Adverse effects of melarsomine are otherwise limited to local inflammation, cough, brief low-grade fever, and salivation. Hepatic and renal toxicity are seldom, if ever, seen.

Laboratory findings associated with adulticidal therapy may include:

Local or disseminated intravascular coagulopathy may occur when platelet counts are < 100,000/mcL. Treatment for severe thromboembolism should include oxygen, cage confinement, a corticosteroid at an anti-inflammatory dosage (eg, prednisone at 1 mg/kg/day, PO), and possibly, low-dose heparin (75–100 U/kg, SC, three times daily) for several days to 1 week. Severe lung injury is likely present if, after 24 hours of oxygen therapy, no improvement is noted and arterial partial pressures of oxygen remain < 70 mm Hg.

The standard melarsomine protocol (two-dose, 24-hour treatment regimen) kills most adult worms, clearing 50%–85% of dogs, whereas the split-dose + doxycycline protocol appears to clear >95% of dogs. Antigen testing should be performed 8–12 months after the final dose of melarsomine. If a positive test result is obtained at this time, consideration can be given to abbreviated retreatment (two injections, 24 hours apart) or a nonarsenical approach with ivermectin or moxidectin/imidacloprid, at preventive dosages. This nonarsenical approach should be preceded by 30 days of doxycycline therapy (10 mg/kg, twice daily) because this minimizes the reaction to dead and dying worms, enhances the kill rate to ~1 year (vs 2.5 years with ivermectin alone) versus the standard slow-kill approach, and is thought to decrease the risk of resistance (see above). The standard "slow-kill" approach with ivermectin alone is against the current recommendations of the American Heartworm Society. Longterm use of macrolides alone to kill adult worms should be avoided because it allows pulmonary pathology to progress during the lengthy period in which worms are dying and being processed.

At specific preventive dosages, the macrolide preventive drugs are effective microfilaricides, although not approved by the FDA for this purpose. Adverse reactions may occur in dogs with high microfilarial counts, depending on the type of macrolide given. However, the microfilarial count is usually lower, and mild adverse reactions occur in ~10% of dogs. Most adverse reactions are limited to brief salivation and defecation, occurring within hours and lasting up to several hours.

Dogs, especially small dogs (< 10 kg), with high microfilariae counts may develop tachycardia, tachypnea, pale mucous membranes, lethargy, retching, diarrhea, and even shock. Treatment includes an IV balanced electrolyte solution and a soluble corticosteroid. Recovery is usually rapid when treatment is administered quickly. Microfilarial tests are no longer routinely performed, and thus severe reactions are seldom expected.

Treatment specifically targeting circulating microfilariae has historically been undertaken 3–4 weeks after adulticide administration. The current practice is to start a macrocyclic lactone for prevention and microfilarial eradication at the time of diagnosis. Although all macrocyclic lactones have microfilaricidal activity and are the safest and most effective drugs available to clear microfilariae, this characteristic varies within the drug group. Only the combination topical product containing imidacloprid and moxidectin is FDA-approved as a microfilaricide. All macrocyclic lactones likely enjoy enhanced efficacy in this regard when accompanied by doxycycline. Livestock preparations of these drugs should not be used to achieve higher doses to obtain more rapid results. Performance of a microfilaria test is recommended at the time of diagnosis and 1–3 months after microfilaricidal therapy has begun.

Sporadic resistance of heartworms to the macrocyclic preventive class has been recognized since 2013. All the current molecules used to prevent heartworm disease have been implicated. However, some formulations (moxidectin/imidacloprid) appear to be more effective against some currently recognized resistant isolates than others. There have been isolates from 7 dogs with varying degrees of resistance. There is little evidence of spread outside of the Mississippi Delta region, where resistance was first recognized.

It is important to realize that the current preventives are effective in the vast majority of cases and should not be abandoned. Emphasis should be placed on owner compliance and year-round preventive therapy as well as on alternative methods of HW prevention, including topical and oral mosquito repellant/insecticides, indoor/screened housing, especially at night, and mosquito abatement programs. The role of "slow-kill" macrolide adulticidal therapy in the development of resistance has been suggested, and it should be avoided. If such therapy is unavoidable, it should absolutely be accompanied by 30 days of doxycycline treatment at the outset, with assurance that microfilariae are eradicated.