Current Advice on Parasite Control:
Heartworm - Canine Heartworm
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 (307-322 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 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 for males and 25-30 cm 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 (DIC)
- 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 heartworm disease can be found in most geographical areas. More than 70 species of mosquitoes are capable of transmitting the disease.
- Transmission can occur anytime infected mosquitoes are active and feeding.
- Rare instances of transmission of microfilaria from infected bitches to fetuses via the placenta and from dog to dog via blood transfusion can occur. However, these microfilariae will not develop into adult worms. Presence of these microfilariae can confound a diagnosis and may serve as a potential source of microfilaria that could be transmitted by feeding mosquitoes.
Although the domestic dog is the primary host for heartworm, other species have been infected, including the following:
- wild canidae, such as coyotes, wolves, foxes, etc.
- domestic cats
- wild felidae, such as mountain lions, bobcats, tigers, etc.
- marine mammals
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.
Dogs on heartworm prevention should be checked annually for the presence of circulating heartworm antigen to verify that they are being protected, and in areas where resistance may be a possibility (see below), it may be prudent to test outdoor dogs twice each year.
- 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 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 serologic testing, 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 a positive test in animals from hypoendemic areas or animals on preventives. Similarly, a negative test in an animal exhibiting clinical signs of heartworm disease should be repeated. Repeat tests should be submitted to a reference laboratory for testing with a test that is different from the original test.
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 reconditum. The following table compares characteristics of the two species; these guidelines are useful only 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 307 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.
- Dogs on heartworm prevention should be checked annually for the presence of circulating heartworm antigen to verify that they are being protected, and in areas where resistance may be a possibility (see below), it may be prudent to test outdoor dogs twice each year.
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 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 has shown that there are isolates of heartworms that are capable of developing to adults in dogs receiving routine prophylaxis with any of the available macrocyclic lactones.
- INFECTED DOGS MUST BE TREATED PROMPTLY WITH AN APPROVED ADULTICIDE (see below) AND UNINFECTED DOGS SHOULD BE MAINTAINED ON ML PREVENTIVES YEAR-ROUND TO PROTECT THEM AGAINST HEARTWORM INFECTION. It is extremely important, however, to do annual antigen testing on dogs receiving preventives 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 highly 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 and eliminate adult heartworms and microfilariae.
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 prevent infection with new larvae if the dog is bitten by more infected mosquitoes because the 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 confirm that delaying treatment while maintaining dogs on preventives improves clearance of worms with subsequent adulticide treatment.
Infected dogs are staged by veterinarians into 1 of 3 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. If the dog is not antigen negative in 4 months, the treatment can be repeated.
- 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 makes this approach the treatment of choice for even Stage 1 and 2 dogs. Other, off-label regimens for administration of melarsomine dihydrochloride are not recommended.
- Melarsomine is not proven effective against heartworms younger than 4 months of age. Because dogs may have been bitten over a period of months by infected mosquitoes, the worms in a dog may be of different ages within a given season, and thus, melarsomine treatment may not be completely effective in all situations. This may necessitate additional therapy or alternate therapeutic strategies.
- All dogs that are treated with melarsomine should be antigen tested 4-6 months after completing 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).
- As many as 20% of dogs infected with heartworms will continue to have circulating microfilariae for at least a year or longer when receiving monthly treatment with macrocyclic lactones.
- 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.
Post-adulticide microfilaricidal treatment
- If microfilariae are present after treatment they must be cleared from the circulation. These microfilariae can persist in the presence of very high levels of macrocyclic lactones for more than a year, and if transmitted to mosquitoes and then new dogs put other dogs at risk of infection with resistant phenotypes.
Rapid clearance of microfilariae may be achieved with elevated dosages of macrocyclic lactones.
- When this method is employed, patients with very high microfilaremia, e.g., > 10/high power field by microscopy, should be pretreated with steroids and/or antihistamines and observed for potential adverse reactions.
- Repeated high dosages of multiple macrocyclic lactones does not always clear microfilariae even after adulticide therapy has been successfully completed.
Additional considerations for adulticide and microfilaricidal therapy
- Most filarial nematodes, including D. immitis, harbor obligate, intracellular, gram-negative bacteria belonging to the genus Wolbachia (Rickettsiales).
- Although more research is needed, initial data suggest that the treatment of dogs with doxycycline prior to adulticide therapy may reduce the gross pulmonary pathology that occurs as a result of thromboembolic shower of dead worm fragments, aid in the suppression of microfilarial numbers after adulticide therapy, and interfere with the ability of the microfilariae to infect other dogs after they’ve passed through a mosquito host.
- 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.
- 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 transmission risk for humans.
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.