Current Advice on Parasite Control:
Heartworm - Canine Heartworm
• Annual testing of all dogs for both antigen and microfilariae of heartworm.
• Protect all dogs from heartworm infection by using preventives year round.
• Treat infected dogs with labeled adulticides and microfilaricides (if microfilaria are present) as soon after diagnosis as medically practical.
Life Cycle and Stages
Heartworm Life Cycle
The heartworm life cycle is demonstrated in the figure below:
- Microfilariae reside in the blood of most, but not all, infected canids.
- Microfilariae (300-322 µm x 6.8-7.0 µm) are ingested by feeding female mosquitoes. After two molts (approximately 2 weeks), infective third-stage larvae (L3s) are present in mosquito mouth parts. Development may be slower at cooler temperatures and ceases at temperatures below 57°F. Development progresses in the mosquito relative to ambient temperature; if ambient temperature increases, development will resume.
- L3s (1,000 µm x 40 µm) are deposited on the skin of the dog during subsequent feeding and migrate through the bite wound into the host. Most L3s molt to fourth-stage larvae (L4s) in canine subcutaneous tissues within 1-3 days after infection.
- L4s migrate through tissues for several weeks.
- A final molt to the sexually immature adult stage occurs approximately 2 months (50 to 70 days) after infection.
- The young adults (2-3 cm in length) enter the vascular system and are carried to the heart and pulmonary arteries, arriving as early as 70 days after infection. Final maturation and mating occurs in the pulmonary vessels. By 4 months after infection, the worms in the pulmonary arteries are around 10-15 cm in length. Fully mature adults at 6.5 months after infection reach lengths of 15-18 cm (5-6 in) for males and 25-30 cm (10-12 in) for females.
- Canine hosts typically demonstrate microfilaremia 6 to 7 months after infection.
- Heartworms live approximately 5 to 7 years in the dog.
- Heartworm infection in the dog induces pulmonary endothelial damage, villous proliferation, and activation and attraction of leukocytes and platelets due to live worms as well as thrombosis, granulomatous, and villous inflammation due to dead and/or dying worms.
- Pulmonary vessels may become thickened and tortuous.
- Cardiac output may be reduced. Pulmonary hypertension may lead to compensatory right heart enlargement and right heart failure. Clinical signs include cough, dyspnea, weight loss, ascites, jugular venous distension, exercise intolerance, and arrhythmias.
- Heartworm infection may induce glomerulonephritis and proteinuria secondary to antigen-antibody complex deposition.
- Rarely, ectopic infections of the eye, central nervous system, peritoneal cavity, systemic circulation, or skin have been reported.
Caval syndrome occurs in a small number of cases, typically associated with large numbers of adults in the pulmonary arteries
- Worms may be found in the post cava and right atrium, causing interference with tricuspid valve function. This results in a peracute life-threatening hemolytic anemia and right heart failure.
Associated findings include:
- pallor, weak pulses, tachycardia, and sudden collapse
- hemoglobinemia and hemoglobinuria
- disseminated intravascular coagulopathy
- murmur caused by tricuspid regurgitation auscultated best on right side of thorax
- Surveys indicate that heartworm infections continue to increase in number and geographic distribution.
- The greatest numbers of cases are seen in the southeastern U.S. and the Mississippi River Valley. There is an apparent high level of prevalence documented in northern California.
Host Associations and Transmission Between Hosts
- Mosquito species capable of transmitting heartworms can be found in most geographical areas. More than 70 species of mosquitoes are capable of transmitting heartworm.
- Transmission can occur anytime infected mosquitoes are active and feeding.
- Rare instances of transmission of microfilariae from infected bitches to fetuses via the placenta and from dog to dog via blood transfusion have occurred. These microfilariae will not develop into adult worms without first developing to the L3 stage in a mosquito. However, such microfilariae are problematic because they can confound diagnosis and because they are infectious to mosquito vectors.
- Although the domestic dog is the primary host for heartworm, other species have been infected, including wild canids, ferrets, cats, wild felids, marine mammals, and people; disease caused by heartworm infection in these different hosts varies.
Prepatent Period and Environmental Factors
- Microfilariae appear in circulation 6 to 7 months after introduction of infective larvae (L3). Infection and successful development of heartworm larvae in mosquitoes is dependent on mosquito feeding habits, mosquito longevity, and ambient temperatures.
Site of Infection and Pathogenesis
See Life Cycle and Stages and Disease.
All dogs, including those on heartworm prevention, should be tested annually using both antigen and microfilariae tests. In some areas, testing dogs twice each year may be indicated, particularly in dogs that are highly exposed to mosquitoes.
- Antigen tests detect a glycoprotein found predominantly in the reproductive tract of the female worm. Only mature infections (older than 6 months) with at least one female worm are usually detected. Low worm burdens (fewer than two adult females) and infections with only male worms may not be detected.
- A number of commercial antigen-capture diagnostic tests are available. Formats include well enzyme-linked immunosorbent assay (ELISA) tests, solid substratum ELISA tests, immunochromatograhic (immunomigratory) tests, and colloidal gold agglutination tests
- Heartworm infection and/or disease is confirmed or ruled out in light of antigen detection, microfilarial detection methods, radiography, echocardiography, and/or electrocardiography. These tests may also be used to identify appropriate therapies, monitor the course of the infection or disease, and determine the success of any treatment.
- Due to high specificity (98-100%) of the available tests in dogs with several female worms, it is better to accept than reject a positive test result. Because no test is 100% accurate, it is prudent to repeat positive tests for animals from hypoendemic areas or animals on preventives. Similarly, a negative test for an animal exhibiting clinical signs of heartworm disease should be repeated. Repeat tests can be submitted to a reference laboratory for testing with a test that is different from the original test.
- In the southern United States, samples from as many as 5-10% of dogs provided false-negative on results with antigen tests, possibly due to formation of antigen-antibody complexes. Heat treatment of these samples prior to testing resulted in detection.
- Although helpful when a diagnosis of heartworm is suspected but the initial antigen test is negative, routine heat treatment of all samples prior to testing is not recommended. Although it can improve antigen detection, heat treatment denatures antibodies and is likely to render subsequent antibody detection assays invalid.
- Mixing samples prior to testing is not recommended, because it can block antigen detection through formation of antigen-antibody complexes and it can dilute circulating heartworm antigen below detectable limits.
Clinical pathological parameters
- Clinical pathology changes are not uniquely diagnostic for heartworms.
- Hematological changes associated with heartworm infection include eosinophilia, basophilia, neutrophilia, nonregenerative anemia, and thrombocytopenia.
- Biochemical changes may include elevated liver enzymes, azotemia, and hyperbilirubinemia.
- Urinalysis may indicate proteinuria and albuminuria.
Detection of microfilariae
Microfilariae are not present in all heartworm-infected dogs. Dogs may be microfilariae negative (“occult”) for several reasons:
- single sex adult infections
- elimination of microfilariae by administration of monthly preventives
- host immune responses
- occurrence of circulating antigen prior to microfilariae production (In rare cases, the appearance of microfilariae may precede antigenemia.)
- Microfilariae are not present in all heartworm-infected dogs. Dogs may be microfilariae negative (“occult”) for several reasons:
Microfilariae may be identified microscopically by several methods:
- direct examination of fresh blood or blood treated with an anticoagulant
- examination of liquid-cell interface (buffy coat) in a microhematocrit tube
- concentration using a stained or unstained Millipore filter
- concentration by centrifugation using the modified Knott procedure
- Antigen tests
Microfilariae of D. immitis must be differentiated from those of Acanthocheilonema (=Dipetalonema) reconditum and, rarely in the U.S., from other Dirofilaria spp. The following table compares characteristics of D. immitis and A. reconditum; these guidelines are only useful with fresh blood samples.
Species Number in blood Motion Shape Length (modified Knott test) Acanthocheilonema reconditum Usually few Progressive Curved body, blunt head, curved or “button-hook” tail 250 to 288 µm Dirofilaria immitis Usually many Stationary Straight body and tail, tapered head 300 to 322 µm
Radiographic evidence of heartworm infection consists of changes to the pulmonary arteries (increased size, tortuosity, and pruning) and right-sided cardiomegaly (evidenced by a reverse “D” shape to the heart).
Pulmonary parenchyma should be evaluated for infiltrates and nodules.
Additional radiographic findings may include lymphadenopathy and pleural effusion.
Radiographic lesions are more pronounced in the caudal lung lobes.
- All dogs, including those on heartworm prevention, should be tested annually using both antigen and microfilariae tests. In some areas, testing dogs twice each year may be indicated, particularly in dogs that are highly exposed to mosquitoes.
Control and Prevention
- Heartworm infection is prevented by the routine administration of a number of macrocyclic lactone preventives.
- These preventives vary in their claims against other internal and external parasites and are available in different formulations (tablets, topicals and injectable preparations).
Macrocyclic lactone (a.k.a., macrolide) preventives currently available include (Visit CAPC’s “Parasite Product Applications For Dogs” webpage):
- ivermectin – oral
- milbemycin oxime – oral
- moxidectin – topical or injectable
- selamectin – topical
RESISTANCE - Recent work indicated that some heartworm isolates can develop to adults in dogs receiving routine prophylaxis with any of the available macrocyclic lactones; though such infections in treated dogs resulted in different heartworm numbers, depending on the preventive used.
- Infected dogs must be treated promptly with an approved adulticide (see below) and unifected dogs should be maintained on macrolide preventives year round to protect them against heartworm infection.
- Annual antigen testing on dogs receiving preventives is extremely important, to verify that they are not becoming infected despite precautions. Annual testing will ensure that infected dogs are detected and treated as soon as possible. For dogs living in high endemic areas, twice-a-year testing is advised.
- At this time, the geographic extent of these resistant heartworms is not known.
The goals of treatment are to address the clinical condition of the animal, to eliminate adult heartworms that cause disease, and to eliminate microfilariae that are infectious to mosquitoes that can vector the infection to other hosts, including back to the treated dog.
Stabilize dogs presenting with clinical heartworm disease. Any or all of the following may be medically indicated:
- corticosteroid therapy
- fluid therapy
- positive inotropic agents
- Dogs receiving a macrocyclic lactone should be maintained on preventive if it is already being administered. If a dog is not receiving a macrocyclic lactone preventive, administration of preventive should be instituted as soon as any severe medical condition has been stabilized. The purpose of preventive use is to kill recent infections of new larvae that can be transmitted by additional infected mosquitoes, preventing the development of additional adult heartworms. Treatment with melarsomine for removal of adult worms will not kill newly introduced larvae.
- CAPC recommends treating infected dogs with adulticide promptly, as soon as medically practical. Delaying treatment while maintaining dogs on preventives may contribute to selection for resistance, allows pathology to progress, and, when treatment is delayed for several months, could lead to more infected dogs remaining untreated if practical concerns interfere with completing an extended treatment protocol. No experimental studies have been conducted to determine if delaying treatment while maintaining dogs on preventives improves clearance of worms with subsequent adulticide treatment.
Infected dogs are staged by veterinarians into one of three classes based on clinical signs: asymptomatic or mild disease (stage 1), moderate disease (stage 2), or severe disease (stage 3).
- For Stage 1 and 2 dogs, melarsomine dihydrochloride (2.5 mg/kg) can be administered intramuscularly twice over a 24-hour period, followed by at least 1 month of strict exercise restriction. This treatment regimen will kill greater than 90% of the worms present and clear a similar percentage of dogs of their infections. The treatment can be repeated for dogs that remain antigen-positive 4 months after the previous treatment.
- The prescribed method for treating Stage 3 dogs is to administer melarsomine dihydrochloride (2.5 mg/kg) intramuscularly once, followed in 1 month (or longer if the dog’s condition dictates) by two intramuscular injections (2.5 mg/kg each) 24 hours apart. Any excitement or exercise beyond slow walking for should be restricted for at least 1 month following each set of injections. This treatment regimen will kill up to 98% of the worms present.
- The greater efficacy obtained using the 3-injection regimen developed for Stage 3 dogs also makes this approach the treatment of choice for Stage 1 and 2 dogs. Other, off-label regimens for administration of melarsomine dihydrochloride are not recommended.
- Melarsomine is not effective against heartworms younger than 4 months of age. Because infected mosquitoes can bite dogs over a period of months, heartworms of different ages can be present within a given season. Thus, melarsomine treatment may not be completely efficacious in all situations, which may necessitate additional therapy or alternate therapeutic strategies.
- All melarsomine-treted dogs should be antigen tested 4-6 months after therapy to determine if infection has been cleared.
Adulticidal therapy using long-term macrocyclic lactone administration - the “slow kill” method - is not recommended, especially in light of resistance! It has been demonstrated that repeated macrocyclic lactone administration over a period of time to infected dogs increases the proportion of circulating microfilariae that possess resistance markers (i.e., application of long-term drug pressure will select for survival of drug-resistant microfilariae).
- Depending on the macrocyclic lactone used, as many as 20% of adult heartworm-infected dogs will continue to have circulating microfilariae for at least a year or longer when receiving monthly preventative.
- In a recent study, false-negative antigen test results were observed for approximately half of dogs managed with slow-kill protocols, presumably because of antigen-antibody complex formation. Antigen test results from dogs on slow-kill may not be a reliable indicator of infection status.
- Although the “slow-kill” method should be avoided, if it is the only medically acceptable option, microfilariae should be eliminated prior to exposure to preventive doses of macrocyclic lactones.
- Topical moxidectin/imidacloprid is label approved in dogs for removal of microfliariae when used monthly.
Post-adulticide microfilaricidal treatment
- When microfilariae are present after treatment, they must be cleared from the circulation. Microfilariae can persist for more than a year in the presence of very high levels of some macrocyclic lactones, and these microfilariae put other dogs at risk of infection (or re-infection) with potentially resistant phenotypes.
Clearance of microfilariae may be achieved with:
- Moxidectin/imidacloprid is indicated for the treatment of Dirofilaria immitis circulating in heartworm-positive dogs.
Additional considerations for adulticide and microfilaricidal therapy
- Most filarial nematodes, including D. immitis, harbor obligate, intracellular, gram-negative bacteria belonging to the genus Wolbachia (a rickettsial symbiont).
- Although more research is needed, initial data suggest that the treatment of dogs with doxycycline prior to adulticide therapy may i) reduce the gross pulmonary pathology that occurs as a result of thromboembolic shower of dead worm fragments ii) decrease the number of microfilariae after adulticide therapy, and iii) interfere with the ability of the microfilariae to develop into infective larvae in mosquito vectors. Importantly, further investigations are needed to test each of these hypotheses.
- Stabilize dogs presenting with clinical heartworm disease. Any or all of the following may be medically indicated:
Public Health Considerations
- Dirofilaria immitis is of public health concern even though the number of reported cases is small.
- More than 100 human cases of pulmonary dirofilariasis have been reported in the United States in the last fifty years.
- Human heartworm Infections have also been recorded in the eye, skin, testicle, and elsewhere.
Human dirofilariasis results in nodular inflammation of the lungs.
- Pulmonary nodules are usually solitary and form around dead immature heartworms.
- Nodules are often mistaken for lung tumors or tuberculosis, resulting in unnecessary surgery.
Prevention is best accomplished through mosquito abatement programs (including screening outdoor kennels), and by using mosquito repellents, wearing protective clothing, and remaining indoors during mosquito feeding periods.
- Reducing the prevalence of heartworm infection in the definitive canine host will also reduce the risk of D. immitis transmission to people.
Blagburn BL, Carmichael J, Kaminsky R, Schenker R, Kaplan R, Moorhead A, Prichard R, Geary T, Bourguinat C, Malone J, Bowman DD. 2013. Resistance and heartworm preventives: historical perspective and overview of research. ABSTRACT 28, 58th Annual Meeting of the American Association of Veterinary Parasitologists, Chicago, IL, July 20-23.
Blagburn BL, Dillon AR, Arther RG, Butler JM, Newton JC. 2011. Comparative efficacy of four commercially available heartworm preventive products against the MP3 laboratory strain of Dirofilaria immitis. Vet Parasitol. 176(2-3):189-94.
Bowman DD. 2012. Heartworms, macrocyclic lactones, and the specter of resistance to prevention in the United States. Parasit Vectors. 5:138.
Bowman DD, Atkins CE. 2009. Heartworm biology, treatment, and control. Vet Clin North Am Small Anim Pract. 39(6):1127-58
Lee AC, Montgomery SP, Theis JH, Blagburn BL, Eberhard ML. 2010. Public health issues concerning the widespread distribution of canine heartworm disease. Trends Parasitol. 26(4):168-73.
Little SE, Munzing C, Heise SR, et al. 2014. Pre-treatment with heat facilitates detection of antigen of Dirofilaria immitis in canine samples. Veterinary Parasitol. 203(1-2):250-2.