Marisa K. Ames
DVM, DACVIM (Cardiology)
Dr. Ames received her DVM from The Ohio State University. Following a rotating internship at Michigan State University and an emergency/critical care internship at Tufts University, Dr. Ames completed a cardiology residency and the Jane Lewis-Seaks post-doctoral research fellowship at North Carolina State University. She spent 7 years as a professor of cardiology at Colorado State University. She is currently an associate professor of cardiology at the University of California, Davis. Her research interests include neurohormonal activation in cardiovascular and kidney disease (specifically the pharmacologic modulation of the renin-angiotensin-aldosterone system) and heartworm disease. She also serves on the executive board of the American Heartworm Society.
Updated August 2022Read Articles Written by Marisa K. Ames
Based on data from the Companion Animal Parasite Council, in 2021, 1 in every 100 dogs tested in the United States was diagnosed with heartworm (Dirofilaria immitis) infection (HWI). The actual prevalence is likely higher, as dogs receiving little or no veterinary care are not fully represented in these data. Given the increase in interstate transport of dogs between rescue/shelter organizations, HWI affects all practices regardless of geography. Fortunately, highly sensitive and specific antigen tests often make diagnosis of HWI straightforward, most dogs with HWI have no or only mild clinical signs, and infection can be cleared with an arsenical-based adulticide therapy. However, clinical dilemmas do arise during the diagnosis and treatment of HWI.
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Dirofilaria Immitis Lifecycle
After transmission of infective L3 larvae from the mosquito vector, the larvae undergo 2 molts to become immature adults, which penetrate the host’s venous system. Heartworms are then carried to the pulmonary vasculature, with some arriving as early as 2.5 months after infection and most arriving by 6 months. In dogs, heartworms reach sexual maturity approximately 6 months after infection and circulating microfilariae are usually present 6 to 9 months after infection.
Diagnosis of Heartworm Infection
Highly sensitive antigen tests provide rapid cageside confirmation of HWI. Current antigen tests detect a protein found predominantly in the reproductive tract of female heartworms. Antigen is usually detectable by about 6 months post-infection. Testing dogs younger than 6 months is therefore not recommended. Similarly, a dog that has missed preventive doses should undergo antigen and microfilaria testing 6 months after the first missed dose and again 6 months after the window of infection closes (i.e., prevention was restarted).
Ideally, microfilaria testing (modified Knott test, Millipore filter, direct smear, or microhematocrit technique) is performed along with antigen testing to confirm a positive antigen test result or help detect a false-negative result. In any patient with a positive antigen test result, a microfilaria test should be performed to determine microfilarial status, as dogs with large numbers of microfilariae may benefit from a scheduled observation period after the first dose of a macrocyclic lactone.
Dogs that have been treated with macrocyclic lactone preventives are often amicrofilaremic (occult infection). A positive antigen test result accompanied by a negative microfilaria test result should be confirmed with a second antigen test (ideally using a different brand or method) before initiation of adulticide therapy. Possible causes of a false-negative or “no antigen detected” (NAD) result include antigen–antibody complexing, low worm burden, immature or all-male infection, and low number of female heartworms. Heat1 or acid treatment2 helps “unmask” antigen–antibody complexing and may increase test sensitivity in the other scenarios (including all-male infections).3 Heat or acid treatment causes immune complex dissociation in samples where antibody has bound the heartworm antigen, thereby freeing the antigen for detection. Heat-treatment tests are available at many commercial diagnostic labs. Although acid-treatment assays are not yet widely available, this approach has the advantage of requiring less serum than heat treatment.
Heat treatment of serum should be considered in cases where heartworm disease is suspected, yet no antigen is detected, such as a dog with an NAD test result accompanied by D immitis microfilaremia and/or clinical signs/diagnostic test results supportive of HWI, especially when the animal is from an endemic region and is receiving no or inconsistent macrocyclic lactone preventive therapy. Heat treatment is not recommended for routine screening or retesting an animal after adulticide therapy, as the meaning of positive results after adulticide administration is not well established. It may be that conversion from an NAD result to a positive result after heat treatment during adulticide therapy results from detection of low levels of residual antigen released after adult heartworm death rather than accurate detection of live adult heartworms.4 It is also not known if heat treatment leads to detection/cross-reaction of off-target epitopes formed after denaturation. Finally, for kits including additional tests (i.e., tick-borne disease), heat treatment destroys antibodies and invalidates the results of these tests.
Although a complete blood count, serum biochemistry panel, and urinalysis are always advisable to best understand the extent of organ system involvement, a packed cell volume/total solids and biochemistry panel that evaluates albumin, kidney values, and liver enzymes is a reasonable compromise and more affordable. Indications for additional imaging are discussed below. In most dogs, once the diagnosis of HWI is made, the protocol for adulticide treatment may be started, though the timing of the first melarsomine injection may be delayed in very sick dogs.
Radiographs are ideally obtained in dogs with HWI that present with respiratory signs such as cough, tachypnea, or cyanosis. The immune-mediated destruction of microfilariae within the pulmonary microcirculation can result in eosinophilic pneumonitis and an interstitial infiltrate with or without a bronchial infiltrate. Rarely, this inflammation leads to eosinophilic granulomatosis, which is characterized by granuloma formation and bronchial lymphadenopathy.
Pulmonary hypertension is indirectly supported by right ventricular hypertrophy (“reversed D” on ventrodorsal/dorsoventral view), dilation of the main pulmonary artery (bulge at 1 o’clock on the same view), and dilation (with or without truncation and tortuosity) of the branch pulmonary arteries (FIGURE 1). Right-sided heart failure is supported by the finding of hepatomegaly and ascites (loss of serosal detail in the cranial abdomen). Findings supportive of pulmonary thrombosis/embolism include interstitial-coalescing-to-alveolar infiltrates, especially in caudal lung lobes; evidence of consolidation; and regional oligemia.
Echocardiography is not a sensitive screening test for HWI in dogs. Echocardiography does, however, allow investigation of cardiac murmurs and cardiac changes suggestive of pulmonary hypertension. A right-sided systolic murmur may be due to tricuspid valve incompetence caused by disruption by heartworms or pulmonary hypertension and resultant tricuspid insufficiency. With heavy infestations, worms may be visualized as equal signs in the main pulmonary artery and its branches and/or the right heart (FIGURE 2). The finding of heartworms in the right atrium and cavae, in conjunction with evidence of elevated systemic venous pressures and intravascular hemolysis, confirms the diagnosis of caval syndrome.
Acute, severe heartworm-induced pulmonary thrombus/embolism (HW-PTE) and resultant pulmonary hypertension can lead to right ventricular dilation and dysfunction, paradoxical septal motion, and flattening of the interventricular septum. More commonly, the pulmonary hypertension associated with HWI has a more insidious, chronic course, and echocardiographic changes include right ventricular hypertrophy (concentric or mixed when tricuspid insufficiency is present), flattening of the interventricular septum, pulmonary artery dilation (FIGURE 2), and right atrial dilation. Measurement of tricuspid or pulmonary insufficiency velocities also allows estimation of pulmonary artery pressures.
Clinical pathology findings include eosinophilia and basophilia and, less commonly, neutrophilia, anemia (usually mild, unless caval syndrome is present), thrombocytopenia (most common 1 to 2 weeks after adulticide therapy), and hyperglobulinemia. Hemoglobinuria and anemia in a dog with HWI are supportive of caval syndrome. Renal lesions and proteinuria have been documented in both dogs and cats with HWI and are likely due to antigen–antibody deposition in the glomerulus. Findings of hypoxemia, hypocapnia, increased alveolar–arterial oxygen gradient on arterial blood gas analysis, and significant elevation in D-dimers (>1000 ng/mL) add support for the diagnosis of HW-PTE. Fluid analysis of cavitary effusions (usually ascites) resulting from right-sided heart failure most often identifies a modified transudate. Cytology from tracheobronchial washing may be suggestive of parasitic infection (with eosinophils as the predominant cell type); however, this is not specific for infection with D immitis.
Arsenical Adulticide Therapy
The treatment protocol recommended by the American Heartworm Society (AHS) advocates administration of a monthly macrocyclic lactone (e.g., ivermectin, moxidectin) and a 28-day course of doxycycline (10 mg/kg PO q12h) at the time of diagnosis, with injection of melarsomine (2.5 mg/kg IM, given deep into an epaxial muscle) on days 60, 90, and 91.5 Melarsomine is highly effective and, when paired with doxycycline, likely clears most (>95%) dogs of HWI.
Administering the combination of doxycycline and ivermectin before melarsomine injection has been found to decrease post-adulticide pulmonary parenchymal and arterial pathology in experimentally infected dogs.6 This is likely due to the combination of the slowly adulticidal macrocyclic lactone and Wolbachia-static/-cidal doxycycline leading to a reduction in Wolbachia numbers and worm mass, ultimately resulting in less antigen extrusion at the time of worm death. An insecticide-repellent product that targets mosquitoes can also be utilized to add protection in highly endemic areas and to prevent heartworm transmission to additional dogs.
The delay prior to giving the melarsomine injections has been called the susceptibility gap. This delay was instituted to allow tissue-phase heartworms (L3, L4, and immature adult) to mature before adulticide administration, as mature heartworms are the most susceptible to melarsomine. Doxycycline narrows this gap, as it is effective at killing migrating tissue-phase heartworms (L3, L3 to L4 molt, and L4).7 It can be argued that an extra 30-day delay further reduces complications, as additional time allows for further degradation of worm biomass and dissipation of Wolbachia surface proteins and other antigens prior to the melarsomine injection. The current AHS-recommended protocol retains this delay.
If the 3-dose AHS protocol is not possible, 2 melarsomine injections (2.5 mg/kg IM) 24 hours apart, ideally after a 28-day course of doxycycline (10 mg/kg PO q12h), are likely the next-best option. When melarsomine is used without doxycycline in a 2-dose protocol, it kills approximately 90% of worms and clears approximately 70% to 80% of dogs with experimental infection. Advantages of this protocol for shelter or rescue operations include lower cost and adulticide use, and the protocol can be started soon after diagnosis, increasing the likelihood that the dog receives the entire treatment. An antigen test should be repeated 9 months after the last melarsomine injection. As noted above, heat-treating serum to disassociate heartworm antigen–antibody complexes should not be used to recheck melarsomine-treated dogs.
Nonarsenical Adulticide Therapy
The well-studied melarsomine-based adulticide treatment is generally believed to be the best approach to treating mature HWI. Objections to alternative (nonarsenical or slow-kill) methods using a macrocyclic lactone and doxycycline include speed of worm death being slower than with melarsomine, allowing for a longer duration of tissue damage; potential contribution to resistance; and inadequate study of these protocols. There are situations, however, in which the use of a macrocyclic lactone at preventive or enhanced dosages and paired with doxycycline may be the best or only adulticidal strategy for a given dog. Instances in which arsenical adulticide may be impossible, contraindicated, or less desirable include:
- During stabilization of severe heartworm-induced cor pulmonale or after worm extraction in caval syndrome
- Comorbid condition conferring guarded to grave prognosis
- Comorbid condition making deep epaxial injection of melarsomine undesirable
- Historic, life-threatening adverse reaction to melarsomine injection
- Regional unavailability of arsenical therapy
Studies to date have shown that moxidectin and ivermectin have better adulticidal effect than selamectin and milbemycin. Doxycycline likely increases the efficacy of a macrocyclic lactone–based adulticide regimen. Several small studies have evaluated the combination of ivermectin or moxidectin (topical and injectable) and doxycycline in dogs with experimental and natural infections.8-13 Although the macrocyclic lactone–doxycycline protocols used in these studies appear to be safe and rendered most dogs NAD on a conventional antigen test within 1 year, larger prospective studies are still needed. HW-PTE is still possible, and exercise restriction should be imposed for months when using a nonarsenical protocol.
An additional consideration, regardless of adulticide strategy, includes the clearance of microfilariae to reduce disease transmission and resistance selection. Imidacloprid/moxidectin is currently the only macrocyclic lactone preventive formulation labeled to kill microfilariae. Doxycycline speeds the clearance of microfilariae when given concurrently with ivermectin (and likely other macrocyclic lactones) and renders any resulting L3 noninfective.14 Care should be exercised when preventives are administered to dogs with heavy microfilarial burdens. This care ranges from observation at home on the day of administration to hospitalization with or without pretreatment with corticosteroids and antihistamines.
Complications and Severe Heartworm Disease
Although most dogs with HWI have no or only mild symptoms, complications may arise during HWI and its treatment. The management of severe heartworm disease has been recently reviewed elsewhere.15
Note: This article is adapted and updated from the NAVC’s 2022 VMX Conference Proceedings.
1. Little SE, Munzing C, Heise SR, et al. Pre-treatment with heat facilitates detection of antigen of Dirofilaria immitis in canine samples. Vet Parasitol. 2014;203(1-2):250-252. doi: 10.1016/j.vetpar.2014.01.007
2. Starkey LA, Bowles JV, Blagburn BL. Comparison of acid- versus heat-treatment for immune complex dissociation and detection of Dirofilaria immitis antigen in canine plasma. Vet Parasitol. 2020;282:109134. doi: 10.1016/j.vetpar.2020.109134
3. Gruntmeir JM, Longa MT, Blagburn BL, Walden HS. Canine heartworm and heat treatment: an evaluation using a well based enzyme-linked immunosorbent assay (ELISA) and canine sera with confirmed heartworm infection status. Vet Parasitol. 2020;283:109169. doi: 10.1016/j.vetpar.2020.109169
4. Savadelis MD, Roveto JL, Ohmes CM, et al. Evaluation of heat-treating heartworm-positive canine serum samples during treatment with Advantage Multi® for Dogs and doxycycline. Parasit Vectors. 2018;11(1):1-8. doi: 10.1186/s13071-018-2685-z
5. American Heartworm Society. Current canine guidelines for the prevention, diagnosis, and management of heartworm (Dirofilaria immitis) infection in dogs. Revised 2018. Accessed July 14, 2022. heartwormsociety.org/veterinary-resources/american-heartworm-society-guidelines
6. Kramer L, Grandi G, Passeri B, et al. Evaluation of lung pathology in Dirofilaria immitis-experimentally infected dogs treated with doxycycline or a combination of doxycycline and ivermectin before administration of melarsomine dihydrochloride. Vet Parasitol. 2011;176(4):357-360. doi: 10.1016/j.vetpar.2011.01.021
7. McCall JW, Kramer L, Genchi C, et al. Effects of doxycycline on early infections of Dirofilaria immitis in dogs. Vet Parasitol. 2011;176(4):361-367. doi: 10.1016/j.vetpar.2011.01.022
8. Grandi G, Quintavalla C, Mavropoulou A, et al. A combination of doxycycline and ivermectin is adulticidal in dogs with naturally acquired heartworm disease (Dirofilaria immitis). Vet Parasitol 2010;169(3-4):347-351. doi: 10.1016/j.vetpar.2010.01.025
9. Savadelis MD, Ohmes CM, Hostetler JA, et al. Assessment of parasitological findings in heartworm-infected beagles treated with Advantage Multi® for dogs (10% imidacloprid + 2.5% moxidectin) and doxycycline. Parasit Vectors. 2017;10(1):245. doi: 10.1186/s13071-017-2190-9
10. Genchi M, Vismarra A, Lucchetti C, et al. Efficacy of imidacloprid 10%/moxidectin 2.5% spot on (Advocate®, Advantage Multi®) and doxycycline for the treatment of natural Dirofilaria immitis infections in dogs. Vet Parasitol. 2019;273:11-16.
11. Ames MK, VanVranken P, Evans C, Atkins CEl. Non-arsenical heartworm adulticidal therapy using topical moxidectin-imidacloprid and doxycycline: A prospective case series. Vet Parasitol. 2020;282:109099. doi: 10.1016/j.vetpar.2020.109099
12. Alberigi B, Fernandes JI, Paiva JP, et al. Efficacy of semi-annual therapy of an extended-release injectable moxidectin suspension and oral doxycycline in Dirofilaria immitis naturally infected dogs. Parasit Vectors. 2020;13(1):503. doi: 10.1186/s13071-020-04380-z
13. Jacobson LS, DiGangi BA. An accessible alternative to melarsomine: “Moxi-Doxy” for treatment of adult heartworm infection in dogs. Front Vet Sci. 2021;8:702018. doi: 10.3389/fvets.2021.702018
14. McCall JW, Kramer L, Genchi C, et al. Effects of doxycycline on heartworm embryogenesis, transmission, circulating microfilaria, and adult worms in microfilaremic dogs. Vet Parasitol. 2014;206(1-2):5-13. doi: 10.1016/j.vetpar.2014.09.023
15. Ames MK, Atkins CE. Treatment of dogs with severe heartworm disease. Vet Parasitol. 2020;283:109131. doi: 10.1016/j.vetpar.2020.109131