Heartworm disease (dirofilariasis), produced by Dirofilaria immitis, primarily affects the pulmonary arteries, producing inflammation, vascular dysfunction, and pulmonary hypertension. Secondarily, this results in right-side cardiac pressure overload and progressive pulmonary insufficiency. Tertiary problems include aberrant heartworm migration, caval syndrome, coagulopathies (DIC), and heart failure. Most infected dogs are subclinically affected, but the most common clinical signs are weight loss, exercise intolerance, cough, and labored breathing. Prevention, with macrocyclic lactones, is crucial. Clearing a heartworm infection typically requires melarsomine, an organic arsenic compound, administered IM in three injections. Chronic use of certain macrocyclic lactones with doxycycline has also been effective when melarsomine cannot be used or is unavailable.
Commonly affected species:
Dogs
Coyotes
Heartworm disease (dirofilariasis) is caused by the filarial organism Dirofilaria immitis. At least 70 species of mosquitoes can serve as intermediate hosts; Aedes, Anopheles, and Culex are the most common genera acting as vectors.
Patent infections are possible in numerous wild and companion animal species. Wild animal reservoirs include wolves, coyotes, foxes, California sea lions (Zalophus californianus), gray seals (Halichoerus grypus), and raccoons. In companion animals, heartworm infection is diagnosed primarily in dogs and less commonly in cats and ferrets.
Dirofilariasis has been reported commonly in most countries with temperate, semitropical, or tropical climates, including the US, Canada, Australia, Latin America, and southern Europe.
In companion animals, infection risk is greatest in dogs and cats housed outdoors. Although any dog or cat, indoor or outdoor, is capable of being infected, most infections are diagnosed in medium- to large-sized, 3- to 8-year-old dogs living outside in endemic areas.
Infected mosquitoes can transmit heartworm infections to people, but there are no reports of such infections becoming patent. Maturation of the infective larvae may progress to the point where they reach the lungs, become encapsulated, and die. The dead larvae precipitate granulomatous reactions called “coin lesions,” which are visible with thoracic radiography and can mimic the radiographic appearance of lung cancer.
Heartworm infection rates in other companion animals such as ferrets and cats are lower but tend to parallel those in dogs in the same geographic region. No age predilection has been reported in ferrets or cats, but male cats have been reported to be more susceptible than females. Indoor and outdoor ferrets and cats can be infected. Other infections in cats, such as those caused by the feline leukemia virus or feline immunodeficiency virus, are not predisposing factors.
Life Cycle
Mosquito vector species acquire microfilariae (a neonatal larval stage) while feeding on an infected host. Once ingested by the mosquito, microfilariae develop into the first larval stage (L1). They then molt into the second larval stage (L2) and again to the infective third stage (L3) within the mosquito in ~1–4 weeks, depending on environmental temperatures. This development phase requires the shortest time (10–14 days) when the mean ambient temperature is > 27°C (81°F) and the relative humidity is 80%.
When mature, the infective larvae migrate to the labium of the mosquito. As the mosquito feeds, the infective larvae erupt through the tip of the labium, and with a small amount of hemolymph, onto the host’s skin. The larvae migrate into the bite wound, beginning the intramammalian phase of the life cycle. A typical Aedes mosquito can survive the complete development of < 10 larvae per mosquito.
In canids and other susceptible hosts, infective larvae (L3) molt into a fourth stage (L4) in 3–12 days. After remaining in the subcutaneous tissue, abdomen, and thorax for ~2 months, L4 undergo their final molt at day 50–70 into young adults, arriving in the heart and pulmonary arteries ~70–120 days after initial infection.
Only 2.5–4 cm in length on arrival, heartworms rapidly grow within the pulmonary vasculature to adult forms (males ~15 cm long, females ~25 cm). When juvenile heartworms first reach the lungs, blood flow forces them into the more distal small pulmonary arteries of the caudal lung lobes. As the parasites grow, they occupy larger and larger pulmonary arteries, occasionally moving into the right ventricle and even the atrium when the heartworm burden is high. Gravid females produce microfilariae as early as 6 months after infection but more typically at 7–9 months after infection.
Microfilariae are detectable in most infected canids (~80%) not receiving macrolide prophylaxis but only occasionally in those dogs placed on preventive after having been infected. The number of circulating microfilariae does not correlate well to the adult female heartworm burden. Adult heartworms typically live 3–5 years, whereas microfilariae may survive for up to 2 years in a dog.
Most dogs are highly susceptible to heartworm infection, and most (mean 56%) experimentally administered infective larvae (L3) develop into adults. Ferrets and cats are susceptible hosts, but the infection success rate is low (an average of 6% in cats and 40% in ferrets).
In cats, the adult burden is often only one to three heartworms. Early death of juvenile heartworms on arrival at the pulmonary vasculature appears to be largely responsible for heartworm-associated respiratory disease (HARD) syndrome in cats. HARD does not require maturation of heartworms but is due to the body’s response to dying and dead immature heartworms. When maturation does occur, adult heartworm survival in cats is typically not longer than 2–3 years. In all animals capable of being infected, aberrant larval migration may occur, resulting in parasitic lesions in the CNS, eye, scrotum, peritoneal cavity, and systemic arterial system as well as in visceral and subcutaneous sites.
Pathogenesis
The severity of cardiopulmonary pathologic changes in dogs is determined by the following factors:
Heartworm numbers and health
Host immune response
Duration of infection
Host activity level
Live, adult heartworms cause direct mechanical trauma, and other suspected factors (eg, antigens and excretions) are thought to directly irritate or to stimulate the hosts’ immune system. This damages vessel intima, leading to proliferative endarteritis and perivascular cuffing with inflammatory cells, including infiltration of high numbers of eosinophils.
Live heartworms seem to have an immunosuppressive effect; however, the presence of dead heartworms leads to more severe vascular reactions and subsequent pathologic changes in the lung, even in areas of the lung not directly contacting the dead heartworms.
Longterm infections—due to direct irritation, heartworm death, and immune response—result in chronic lesions and subsequent scarring.
Active dogs tend to more often develop pulmonary hypertension than inactive dogs for any given heartworm burden. Frequent exertion increases pulmonary arterial pathologic changes and increases pulmonary artery resistance (with resultant pulmonary hypertension) and thereby may precipitate overt clinical signs, including congestive heart failure (CHF).
High heartworm burdens are most often the result of infections acquired from numerous mosquito exposures. High exposures in young, naive dogs in temperate climates can result in severe infections, possibly precipitating vena cava (caval) syndrome the year after.
In general, because of the heartworm size and smaller dimensions of the pulmonary vasculature, small dogs do not tolerate infection or treatment as well as large dogs.
Heartworm-associated inflammatory mediators that induce immune responses in the lungs and kidneys (eg, immune complex glomerulonephritis) cause vasoconstriction and possibly bronchoconstriction. Leakage of plasma and inflammatory mediators from small vessels and capillaries causes parenchymal lung inflammation and mild, noncardiogenic edema formation. Pulmonary artery disease compromises vascular compliance, and this, with decreased ability to adequately vasodilate, results in increased flow velocity, especially with exertion, and resultant shear stresses further damage the endothelium. The process of endothelial damage, vascular dysfunction, increased flow velocity, and local ischemia is a vicious cycle. Inflammation with ischemia can result in irreversible interstitial fibrosis.
Pulmonary arterial pathologic lesions in cats and ferrets are similar to those in dogs; however, the small arteries develop more severe muscular hypertrophy. Nevertheless, pulmonary hypertension with CHF is less common in cats than in dogs or ferrets. Arterial thrombi, thromboemboli, and living or dead heartworms become lodged within pulmonary arteries or arterioles, resulting in vascular remodeling with transient or permanent, complete or partial, obstruction. In cats, parenchymal changes associated with dead heartworms differ from those observed in dogs and ferrets. Rather than type I alveolar cell damage, as found in dogs, cats develop type II alveolar cell hyperplasia, which can act as a major barrier to oxygenation. Most important, because of restricted pulmonary vascular capacity and subsequent pathologic changes, ferrets and cats are more likely than dogs to die as a result of heartworm infection.
Wolbachia
Courtesy of Dr. Laura Kramer.
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 treatment, which has become an important part of the armamentarium against heartworms.
Clinical Findings
In dogs, heartworm infection is ideally identified by serologic testing before onset of clinical signs; however, at the earliest, heartworm antigenemia and microfilaremia do not appear until ~5 and 6.5 months after infection, respectively. When dogs do not receive preventive medication and are not appropriately tested, infection and disease progress undetected.
Clinical signs of heartworm infection include the following:
cough
exercise intolerance
unthriftiness
cyanosis
dyspnea
hemoptysis
syncope
collapse
ascites (right-side CHF)
The frequency and severity of clinical signs correlate to the extent of lung pathologic changes and the amount of animal activity. Signs are often not observed in sedentary dogs, even though the heartworm burden may be relatively high. Infected dogs experiencing a dramatic increase in activity, such as during hunting seasons, may develop overt clinical signs. Likewise, heartworm death and thromboemboli precipitate clinical signs.
Dogs 5–7 years old are at higher risk of having a heavy heartworm burden, presumably because of increased time of exposure and opportunity for disease development. Other concurrent health factors (eg, concurrent cardiopulmonary or other organ system disease) affect risk assessment. The extent to which exercise can and will be restricted during the recovery period is another important consideration.
The severity of clinical signs in infected dogs is classified into four stages ( See table Stages of Heartworm Infection in Dogs). Stage IV includes dogs with caval syndrome, in which retrograde migration of heartworms into the right ventricle and atrium and caudal and cranial vena cavae precipitates tricuspid valve insufficiency on top of severe pulmonary hypertension. The resulting low-output heart failure, hemolysis with pigmenturia, anemia, and hepatorenal dysfunction merge to produce an often terminal crisis.
Stages of Heartworm Infection in Dogs
Stage | Signs |
|---|---|
I | Minimal, if any, signs and none evident to owner |
II | Mild to moderate signs, most often including cough |
III | Severe signs, including respiratory signs, weight loss, exercise intolerance, and even heart failure |
IV | Caval syndrome |
Courtesy of the University of Florida.
Courtesy of the University of Florida.
Courtesy of the University of Florida.
Courtesy of the University of Florida.
Clinical Findings in Cats and Ferrets
Cats infected with heartworm may be subclinically affected 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.
When evident, clinical signs in cats usually develop during two phases of the heartworm life cycle: the arrival of juvenile heartworms in the pulmonary vasculature ~3–4 months after infection, and the death of adult heartworms. The term HARD refers to signs of immature heartworm infection.
The early signs are associated with an acute vascular and parenchymal inflammatory response to the newly arriving young heartworms and the subsequent death of many or all of these juveniles. This initial phase is often misdiagnosed as asthma or allergic bronchitis.
Results of heartworm antigen tests in such cats are negative (measured antigens are associated with mature female heartworms) during the early eosinophilic pneumonitis syndrome, although results of antibody tests typically are positive.
Although not yet well characterized, clinical signs are believed often to resolve, and they may not reappear or may be silent for months. HARD has been postulated to contribute to longterm lung damage, but this has yet to be demonstrated conclusively.
Cats harboring mature heartworms 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 or anaphylactic-like shock.
Ferrets, more so than cats, mimic canine heartworm infection in terms of clinical signs. The large parasite:host body weight ratio dictates that ferrets (and cats) develop clinical signs with relatively small heartworm burdens. Ferrets with heartworm disease may demonstrate one or more of the following signs:
Weight loss
Fatigue
Cough
Rapid or labored breathing
Heart murmur
Distended and pulsatile jugular veins (CHF)
Gray and cold mucous membranes
Ascites
Pleural effusion
Fainting
Sudden death
See table Diagnostic Tests, Clinical Signs, and Treatment for Heartworms in Dogs, Cats, and Ferrets
Diagnostic Tests, Clinical Signs, and Treatment for Dirofilariasis in Dogs, Cats, and Ferrets
Host | –-–----------------Diagnosis (Test Utility)--------------------- | Clinical Signs | Prevention | ------------Treatment------------ | ||||
|---|---|---|---|---|---|---|---|---|
Microfilaria | Ag or Ab Test | Thoracic radiography | Echocardiography | Adults | Microfilariae | |||
Dog | **** | ***** (Ag) | *** MPA, PA, RHE, PTE, PIE | ** | Respiratory, weight loss, exercise intolerance, heart failure | Ivermectin, milbemycin, selamectin, or moxidectin | Melarsomine, doxycycline, supportive treatment | Moxidectin,a ivermectin, milbemycin, or selamectin + doxycycline, |
Cat | * | ** (Ag) **** (Ab)# | ** PA, PIE | **** | Respiratory, vomiting, sudden death, heart failure | Ivermectin, milbemycin, selamectin, moxidectin, or eprinomectin | Supportive treatment;, doxycycline + melarsomine, heartworm extraction | NA |
Ferret | * | *** (Ag) | * RH | *** | Heart failure, respiratory, sudden death, heart failure | Ivermectin, milbemycin, selamectin, or moxidectin | Supportive treatment (including corticosteroids) | NA |
aImidacloprid-moxidectin is the only approved microfilaricide. * = rarely useful; ** = somewhat useful; *** = moderately useful; **** = often useful; ***** = excellent test; Ag = antigen; Ab = antibody; # = Ab-positive does not prove mature infection, only exposure/abbreviated infection; MPA = main pulmonary artery enlargement; PA = pulmonary artery enlargement; PTE = pulmonary thrombus/thromboembolus; PIE = pulmonary infiltrate with eosinophils; ML = macrocyclic lactone (macrolide); RH = right heart enlargement; NA = not applicable Adapted from McCall, JW. Clin Tech Small Anim Pract. 1998;13(2):112. | ||||||||
Diagnosis
Serology: antigen test for cats and dogs, antibody test for cats
Detection of microfilariae: direct smear, modified Knott test, millipore filter technique
Heartworm Detection in Dogs
The antigen detection test is the preferred diagnostic method for routine screening or when seeking verification of a suspected heartworm 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 heartworms. 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 heartworm prophylaxis. For dogs > 7 months old and not on heartworm prophylaxis, testing should be performed at that time and 7–12 months after initiating treatment with preventives. Subsequently, annual antigen detection tests are recommended.
Some experts use the terminology “below detectable limits” in place of "negative results" to underscore the possibility that heartworm-infected pets with a negative test result may convert to a positive result as heartworms mature or that small-burden female infections may produce false-negative results.
The extent of antigenemia is directly related to the number of mature female heartworms present. Most dogs harboring more than two adult female heartworms 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 heartworm 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 result 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 heartworm. Nevertheless, it has value because a small percentage of heartworm-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 result, 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 treatment 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 heartworms 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.
Findings on ECG are usually normal in infected dogs. 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.
Heartworm Detection in Cats and Ferrets
The diagnosis of heartworm infection in cats is based on historical and physical findings, index of suspicion, thoracic radiography, 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 test negative, if no adult heartworms develop. Cats with mature infections are also occasionally found to test temporarily negative, if tested before detectable antigenemia develops. Nevertheless, the antigen test is strongly recommended in cats in which heartworm infection is suspected.
Antibodies to heartworms, produced by 90% of infected cats, often appear by 2–3 months after L3 infection and are generally detectable by 5 months. However, antibodies can persist at detectable concentrations for several months after heartworm death. In addition, 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 result indicates infection by heartworm larval stages, and possibly HARD, but not necessarily a mature infection. In conjunction with other provocative findings, antibody seropositivity is useful in making a clinical diagnosis of heartworm 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 result 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, heartworms can often be visualized by use of echocardiography. This is because of the relative sizes of the heartworms 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 visualized. Parallel hyperechoic lines, produced by the heartworm 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 echocardiography when performed by an experienced operator.
In ferrets, commercial antigen tests have detected heartworm 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 heartworm burdens (cats and ferrets). Furthermore, although microfilaria testing is only rarely helpful, adult heartworms can often be seen with echocardiography and nonselective angiography.
Ancillary Tests in Cats, Dogs, and Ferrets
In addition to antigen, antibody, and microfilaria tests in cats and dogs, a CBC, chemistry profile, urinalysis, and particularly thoracic radiography 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 heartworm-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 (as in cardiac cachexia). Serum ALT and alkaline phosphatase activities 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 concentration 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, radiography can demonstrate cardiac and pulmonary arterial changes compatible with heartworm disease. In addition, adult heartworms can often be seen with echocardiography and nonselective angiography.
Treatment in Dogs
Doxycycline, split-dose melarsomine, and exercise restriction is most effective
Nonarsenical protocols using ivermectin can be used in cases of melarsomine failure or financial constraints
Pretreatment Evaluation
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 heartworm 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 no effective way to determine heartworm burden other than direct echocardiographic visualization. Most cases do not warrant this test.
Before adulticide treatment, heartworm-infected dogs are assessed and rated for risk of postadulticide thromboembolism. Risk can be categorized as follows:
Low risk of thromboembolic complications, light heartworm burden, and no evidence of parenchymal or pulmonary vascular lesions
High risk of thromboembolic complications
Dogs in the low-risk category would ideally fulfill the following conditions: young, with no clinical signs, normal findings on thoracic radiography, a low circulating antigen concentration or a negative antigen test result with circulating microfilariae, no heartworms visualized by echocardiography, and no concurrent disease as well as having owners capable of completely restricting exercise. The low-risk group would also include dogs that have previously undergone adulticide treatment but remain antigen positive (presumed low heartworm burden).
Dogs with near-normal findings on thoracic radiography 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 heartworm infection (eg, coughing, dyspnea, ascites), abnormal findings on thoracic radiography, high circulating antigen concentration, heartworms visualized by echocardiography, concurrent disease, and little or no possibility that the owners will restrict exercise.
After evaluation, risk assessment, and financial consideration, an adulticide treatment is chosen. These approaches ( see Table: Guide to Choosing Heartworm Therapeutic Protocol), listed in order of highest to lowest regarding safety, efficacy, duration of treatment, and cost, are as follows:
Laboratory and radiographic workup, doxycycline, split-dose melarsomine (three doses), exercise restriction
Doxycycline and split-dose melarsomine (three doses), exercise restriction
Split-dose melarsomine (three doses), confinement
Two-dose melarsomine, strict confinement
Nonarsenical adulticide: doxycycline (10 mg/kg, PO, every 12 hours for 4 weeks), with ivermectin, milbemycin, selamectin, or moxidectin given at the preventive dosage every 30 days for 3 months (with decreased exercise)
Nonarsenical adulticide ("slow-kill"): preventive dosage of ivermectin, milbemycin, selamectin, or moxidectin (not advised)
Pretreatment Stabilization
Dogs at high risk of complications should be stabilized before melarsomine administration. Adulticide treatment often precipitates worsening of pulmonary or cardiac signs as heartworms 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 heartworms.
Dogs with right-side CHF should be treated as follows:
Furosemide (1–2 mg/kg, PO, every 12 hours)
Pimobendan (0.25 mg/kg, PO, every 12 hours)
An angiotensin-converting enzyme (ACE) inhibitor such as enalapril (0.5 mg/kg, PO, every 12 hours, increased to 0.5 mg/kg, PO, every 12 hours, after 1 week, pending renal function test results)
Moderate dietary sodium restriction
Abdominal paracentesis, as needed
Sildenafil can be used (1 mg/kg, PO, every 8 hours initially) as a pulmonary vasodilator. Caution is warranted with this and other vasodilators to avoid the adverse effect of systemic hypotension.
Adulticide treatment should be delayed indefinitely in dogs with CHF.
Caval syndrome results from heartworms 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 heartworm-induced tricuspid valve leakage, hemolysis, and damage to the liver and kidneys.
In caval syndrome, removal of heartworms 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 heartworms 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, adulticide treatment is undertaken to eliminate remaining heartworms. Particular care should be taken if many heartworms are still visualized by echocardiography.
Arsenical (Melarsomine) Adulticide Treatment
The only approved heartworm adulticide is melarsomine dihydrochloride, which is variably effective against mature (adult) and immature heartworms of both sexes, with male heartworms 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. The package insert recommendations for needle size for dogs are as follows:
≤ 10 kg: use a 23-gauge, 1-inch needle
> 10 kg: use a 22-gauge, 1.5-inch needle
On each administration, the left and right sides should be alternated, and superficial injection should be avoided. Pressure at the injection site should be applied and maintained for 5 minutes to prevent drug migration.
Approximately one-third of dogs will exhibit local signs of 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 decrease 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 heartworms. Further benefits accrue with the addition of doxycycline treatment.
The current ideal approach to adulticide treatment is to administer doxycycline (10 mg/kg, PO, every 12 hours for 30 days; decreased to 5 mg/kg, PO, every 12 hours if not tolerated) and macrocyclic lactone preventive at the standard preventive dosage and frequency. After 2 months, adulticide 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 decrease pulmonary inflammatory lesions from dying heartworms 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 heartworm death, the second and third injections can be withheld indefinitely.
Dogs with high heartworm burdens are at risk of severe respiratory complications. Because only ~50% of heartworms are killed after the first injection and because heartworm antigenic burden has been lowered by the wolbachiostat doxycycline, the cumulative impact of heartworm emboli on severely diseased pulmonary arteries and lungs is decreased. This approach destroys a higher percentage of adult heartworms than the standard two-dose protocol.
For the utility and advisability of various treatment protocols, see Table: Guide to Choosing Heartworm Therapeutic Protocol.
Guide to Choosing a Heartworm Treatment Protocol
Protocol | Advantages | Disadvantages | Utilitya | |
|---|---|---|---|---|
1 | Split dose (3 injections), melarsomine and doxycycline; thoracic radiography, CBC, UA, chemistry panel, coagulation profile | ↑ efficacy, ↓ risk of PTE, safety of phased heartworm kill, no resistance concern | Cost $$$$; exercise restriction for 2 months | Appropriate for all; best approach for severe heartworm disease |
2 | Standard dose (2 injections), melarsomine and doxycycline; thoracic radiography, CBC, UA, chemistry panel, coagulation profile | ↓ cost, ↓ risk of PTE (vs standard dose), exercise restriction only 1 month, no resistance concern | Cost $$$; ↑ risk of PTE (vs split dose); ↓ kill efficacy (vs split dose) | Appropriate when financial constraints and mild to moderate heartworm disease |
3 | Standard dose (2 injections), melarsomine | ↓ cost; exercise restriction only 1 mo, no resistance concern, easier for shelters | Cost $$; ↑ risk of PTE (vs standard dose); ↓ kill efficacy (vs split dose); cage rest imperative | Appropriate when financial constraints and mild heartworm disease |
4 | Nonarsenical adulticide treatment: ivermectin, milbemycin, selamectin, or moxidectin with doxycycline | ↓ cost, no injections, no hospitalization, shorter treatment duration than slow kill protocol | Cost $; ↑ risk of resistance, not approved by AHS, ~12-month course, lung disease progression, time of heartworm death unknown | Appropriate when there are severe financial or other constraints, lack of melarsomine availability, or failure of melarsomine treatment to clear dog previously |
5 | Slow kill nonarsenical adulticide treatment with ivermectin, milbemycin, selamectin, or moxidectin at preventive dosage | Inexpensive; no injections | ↑ risk of resistance, 30-month course, lung disease progression, time of heartworm death unknown | Should be avoided; MUST clear microfilariae |
a None of these are appropriate for initial management of caval syndrome, but they may be used to complete treatment after heartworm removal. UA = urinalysis; PTE = pulmonary thromboembolism; AHS = American Heartworm Society; $ = relative cost | ||||
Doxycycline in Adulticide Treatment
Doxycycline has become an important part of treatment of heartworm 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 treatment (at 10 mg/kg, PO, every 12 hours for 30 days, or 5 mg/kg, PO, every 12 hours, if not tolerated) in heartworm-infected dogs.
Doxycycline is given in conjunction with ivermectin, milbemycin, selamectin, or moxidectin every 30 days at the preventive dosage. This combination decreases the severity of lung injury after adulticide treatment, probably by decreasing the amount of Wolbachia antigen and the proteins released from the heartworm uterus as the bacteria die and the uterus degenerates.
Doxycycline treatment hastens heartworm death when a “slow-kill” approach is used, thereby presumably decreasing the negative impact of heartworms 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, milbemycin, selamectin, or moxidectin alone. Doxycycline is advocated in treating dogs with heartworm 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 (10 mg/kg, PO, every 12 hours for 30 days) kills developing larvae (L3> L4> young adults), 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 heartworm, which starts at inception of doxycycline treatment, is likely not maximized at one month but is more advanced with another 30 days' time for heartworm degradation. This should further decrease the reaction of the host to dying parasites.
Nonarsenical (Macrolide + Doxycycline) Adulticide Treatment
Cases in which nonarsenical adulticide treatment might be considered include the following:
Melarsomine shortage or lack of access
Previous treatment with one or more courses of melarsomine
Owner concerns: risk, finances
Overriding serious health issues
Previous serious reaction to melarsomine
Owners' inability or unwillingness to keep dog confined
Shelter concerns: financial and time constraints
Although generally agreed that the only FDA-approved approach and the American Heartworm Society's recommendation for treating heartworm 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 treatment, reliance on patient compliance for years, ongoing host damage, and concern for resistance development. More recently, the addition of doxycycline has been shown to decrease the duration of treatment necessary for an ~95+% kill rate from ~2.5 years to ~1 year.
After Adulticide Treatment
After melarsomine injections, 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 adulticide treatment may include the following:
Inflammatory leukogram
Thrombocytopenia
Prolonged activated clotting time or prothrombin time
Increase in serum CK activity
Local or disseminated intravascular coagulopathy may occur when platelet counts are < 100,000 platelets/mcL. Treatment for severe thromboembolism should include oxygen, cage confinement, a corticosteroid at an anti-inflammatory dosage (eg, prednisone at 1 mg/kg, PO, every 24 hours), and possibly, low-dose heparin (75–100 U/kg, SC, every 8 hours) for several days to 1 week. Severe lung injury is likely present if, after 24 hours of oxygen administration, 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 heartworms, 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 treatment (10 mg/kg, PO, every 12 hours), which minimizes the reaction to dead and dying heartworms, enhances the kill rate to ~1 year (vs 2.5 years with ivermectin alone) compared with the standard slow-kill approach, and decreases 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 heartworms should be avoided because it allows pulmonary pathologic changes to progress during the lengthy period in which heartworms are dying and being processed.
Microfilaricide Treatment
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 microfilarial 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 microfilaricide 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 microfilaricide treatment has begun.
Treatment in Cats
There is currently neither a satisfactory nor approved treatment approach for heartworm infection in cats; therefore, all cats in regions endemic for canine heartworm disease should receive drug prophylaxis.
Infections are likely more often lethal in cats than dogs; however, some cats are thought to survive infection without demonstrable clinical signs. The lifespan of adult heartworms in cats is thought to be ~2 years, so spontaneous recovery is possible. Cats may remain subclinically affected, experience episodic vomiting or dyspnea (resembling asthma), die suddenly from either pulmonary thromboembolism or an anaphylactoid reaction, or, rarely, develop CHF.
Because there is no safe or approved adulticide for cats, many are managed conservatively with restricted activity and corticosteroid treatment, such as prednisolone (1–2 mg/kg, PO, every 24–48 hours; dosage minimized as much as possible). Steroids decrease the severity of vomiting and respiratory signs. The hope is that episodes of pulmonary complications will not prove fatal as the heartworms die. Barring consecutive, additional infection, 25%–50% of cats may survive with this approach. Serial antigen and antibody testing (at intervals of 6–12 months) can be used to monitor status.
Although there are no supportive data, administration of doxycycline (10 mg/kg, PO, every 12 hours for 30 days) and ivermectin (24 mcg/kg, PO, every 30 days) could be theorized to cause heartworm degradation and contracture in infected cats, thereby lessening the potential for catastrophic consequences when the heartworms die. The macrocyclic lactone would also protect the cat from additional infection.
Surgical retrieval of heartworms from the right atrium, right ventricle, and vena cavae via jugular venotomy can be attempted in cats in which heartworms are detected by echocardiography. An endoscopic basket, snare, or horsehair brush can also be advanced via the right jugular vein under fluoroscopy. Cats in CHF have been cured by heartworm removal.
Treatment in Ferrets
Treatment in ferrets is, likewise, difficult, because there is no approved agent for this purpose. Treatment with adulticides (thiacetarsemide and melarsomine) has resulted in ~50% mortality rate in ferrets. Moxidectin (injectable and topical formulations) has been widely thought to be adulticidal for heartworms in ferrets and is given at the same dosage and frequency as in dogs. Topical moxidectin and imidacloprid (combination), approved by the FDA for use in ferrets to prevent heartworm infection and to prevent and treat flea infestations, is a logical choice as an adulticidal macrocyclic lactone.
Prevention
Heartworm infection is generally completely preventable with macrolide prophylaxis. Year-round prevention in dogs is advised, beginning at 6–8 weeks of age. No testing is necessary at this age, because the presence of mature female heartworms is required to produce a positive heartworm test (antigen or microfilaria). When prophylaxis is started after 7 months of age, an antigen test and a test for presence of microfilariae is recommended, followed by another antigen test 6–7 months later. This series of tests will help to avoid unnecessary delay in detecting subclinical infections as well as potential confusion concerning effectiveness of the preventive program, because it cannot be determined until the second test whether infection existed before beginning chemoprophylaxis.
Formulations of the macrolide (macrocyclic lactone) heartworm preventive molecules, ivermectin, milbemycin oxime, moxidectin, and selamectin, are safe and effective, as prescribed, for all breeds of dogs. Marketed products may contain additional chemicals covering various parasite spectra, including GI parasites and ectoparasites.
At the approved dosage, milbemycin kills microfilariae quickly, and in the face of high microfilarial concentrations, a shock reaction may occur. Thus, milbemycin should not be administered without close monitoring or prophylactic pretreatment (steroids, antihistamine, or both) as a preventive in dogs with high numbers of microfilariae. All macrocyclic lactones should be used with caution under these circumstances.
Heartworm prevention is also recommended for all cats in endemic regions, regardless of housing status, because of the potential for severe consequences with infection. Performing microfilaria testing in cats before starting prophylaxis is not required, because cats have no or small numbers of microfilariae, and when microfilariae are present, their presence is typically transient. Ivermectin (24 mcg/kg, PO, every 30 days) for cats is safe and effective and is also effective against hookworms. Prophylaxis should be started in kittens at 6 weeks of age and continued lifelong.
Milbemycin oxime flavored tablets (1.3 mg/kg, PO, every 30 days) are approved for use in cats for heartworm prevention and control of hookworms, roundworms, and whipworms.
Selamectin (6 mg/kg, topically, every 30 days) for heartworm prevention in cats also kills adult fleas and prevents flea eggs from hatching for 1 month. It is also indicated for treatment and control of ear mites, sarcoptic mange, , hookworms, and roundworms.
The combination of eprinomectin (~0.12 mg/kg, topically, every 30 days) and praziquantel (~2.0 mg/kg, topically, every 30 days) is used to prevent and treat heartworm, hookworms, roundworms, and tapeworms. This product is labeled for kittens > 7 weeks of age, whereas the others are approved for kittens > 6 weeks of age.
A topical combined formulation of moxidectin and imidacloprid, administered at dosages of 1 mg/kg for moxidectin and ~10 mg/kg for imidacloprid, is effective against heartworm infection and flea infestations. Although all currently marketed preventives are likely effective in ferrets, only topical moxidectin/imidacloprid is approved by the FDA. Importantly, the preventive dosage for ferrets is the same as that for dogs, but not cats.
Resistance
Sporadic resistance of heartworms to the macrocyclic preventive class has been recognized since 2013. All the current molecules used to prevent dirofilariasis 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 amounts of resistance. There is little evidence of spread outside of the Mississippi Delta region, where resistance was first recognized.
Preventives are effective in most cases and should not be abandoned. Emphasis should be placed on owner compliance and year-round prophylaxis, as well as on alternative methods of heartworm prevention, including topical and oral mosquito repellent and insecticides, indoor or screened housing, especially at night, and mosquito abatement programs.
The role of "slow-kill" macrolide adulticide treatment in the development of resistance has been suggested, and it should be avoided. If such treatment is unavoidable, it should absolutely be accompanied by 30 days of doxycycline administration at the outset, with assurance that microfilariae are eradicated.
Key Points
Heartworm disease is preventable in most instances.
Although resistance to macrocyclic lactones is an important threat, its immediate concern is limited and localized to the Mississippi Delta region.
Some form of heartworm adulticide treatment should be offered to all owners of heartworm-infected dogs, other than those with terminal illness or other definite contraindication to treatment.
Cats are at lesser risk than dogs and have a lower infection rate, yet they benefit from heartworm preventives because there are no effective treatments for infection.
Ferrets are also susceptible to heartworm, and treatment of infection is difficult. However, there is an approved preventive medication combination.
