Heartworm

Synopsis

CAPC Recommends

• 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 microfilariae are present) as soon after diagnosis as medically practical.

View forecasts for Heartworm in your local area at https://petdiseasealerts.org.

Species

Dirofilaria immitis

Life Cycle and Stages

• 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. Also, developing larvae in mosquitoes can undergo developmental arrest in some mosquito species if they become inactive (overwinter) during cold weather. Larvae then resume development when mosquito development proceeds.
• 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 and the blood vascular system 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 Lifecycle

Disease

• Live heartworms in the dog induce pulmonary endothelial damage, villous proliferation, and activation and attraction of leukocytes and platelets. Dead and dying heartworms induce thrombosis, granulomatous, and villous inflammation.
• 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.
• Heartworms may induce glomerulonephritis and proteinuria secondary to antigen-antibody complex deposition.
• Heartworms can be found at abnormal locations such as the eyes, central nervous system, peritoneal cavity, peripheral vasculature and skin.
• Caval syndrome (CS) occurs in a small number of cases, and is usually associated with large numbers of adults in the pulmonary arteries
  • Worms present in the post cava and right atrium interfere with the function of the tricuspid valve. CS is a peracute life-threatening condition resulting in hemolytic anemia and right heart failure.
  • Additional 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

Prevalence

• Surveys indicate that heartworm infections continue to increase in number and geographic distribution. The geographic expansion of heartworm infection is caused, in part, by increased efforts to re-locate and re-home dogs (see Drake and Parrish, 2019 in the reference section).

• The greatest numbers of cases are seen in the southeastern U.S. and the Mississippi River Valley.  However, cases are appearing with increasing frequency in traditionally low prevalence areas such as California, Oregon, Washington and Colorado.

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Raw reported heartworm prevalence rates for 2019

Head-banging smoothed heartworm prevalence rates for 2019

Host Associations and Transmission Between Hosts

• At least 25 species of mosquitoes were shown to harbor L3 larvae (see Ledesma and Harrington, 2011 in the reference section). Mosquito species capable of transmitting heartworms can be found in most geographical areas.
• Key criteria for determining if mosquitoes are successful heartworm vectors include:
  • Presence of L3 larvae in wild caught mosquitoes.
  • Vector distribution overlaps areas of high heartworm prevalence in wildlife and domestic canids.
  • Feeding on susceptible vertebrate hosts in nature.
  • High feeding frequency on microfilaremic vertebrate reservoirs in nature.
  • Demonstrated development of L3 larvae in laboratory studies.
• 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 many factors such as mosquito species, mosquito feeding habits, mosquito longevity, and ambient temperatures.

Site of Infection and Pathogenesis

See Life Cycle and Stages and Disease.

Diagnosis

• 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 exposed to high numbers of mosquitoes for long periods.
  • 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. Recent research supports that the diagnostic glycoprotein is produced by male worms but it may be complexed by antibody (see Gruntmeir et al, 2019 in the reference section).
  • A number of commercial antigen-capture diagnostic tests are available. Formats include well enzyme-linked immunosorbent assay (ELISA) tests, solid substratum ELISA tests, and immunochromatograhic (immunomigratory) tests.
• Heartworm infection and/or disease is confirmed or ruled out in light of antigen detection, detection of microfilariae, radiography, echocardiography, and/or electrocardiography. These tests may also be used to identify and select appropriate therapies, monitor the course of the infection or disease, and determine the success of any treatment.
• Laboratory tests
  • Antigen tests
    • Due to high specificity (98-100%) of the most available tests in dogs, it is better to accept than reject a positive test result. Because no test is 100% accurate, it is prudent to repeat positive tests using a different test platform or a test performed at a different site. Similarly, a negative test for an animal exhibiting clinical signs of heartworm disease or circulating D. immitis microfilariae, should be repeated.
    • 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 of antigen (see Little et al, 2014 in the reference section).
    • When a diagnosis of heartworm is suspected but the initial antigen test is negative, heat treatment is recommended. However, heat treatment of all samples prior to testing is not recommended at this time. Although it can improve antigen detection, heat treatment denatures antibodies and will render subsequent antibody detection assays invalid.
    • Mixing 2 or more samples prior to testing is not recommended. Mixing samples can block antigen detection through formation of antigen-antibody complexes or it can dilute circulating heartworm antigen below detectable limits.
  • Clinical pathological parameters
    • Changes in hemogram and chemistry panel are not uniquely diagnostic for heartworms.
    • Hematological changes associated with but not pathognomonic for 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 in advanced cases or CS.
  • 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.)
      • test used to detect microfilariae is not sensitive enough to detect low numbers.
  • 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 test (MKT)

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. The number and type of motion of microfilariae can only be assessed in fresh blood samples. The shape and size of microfilariae are better determined using a Millipore filter test or a MKT.

Acanthoceilonema reconditum

Number in blood: Usually few

Motion: Progressive

Shape: Curved body, blunt head, curved or "button-hook" tail

Length (modified Knott test): 250 to 288 µm

Width: 4.7 to 5.8 µm

Dirofilaria immitis

Number in blood: Usually many

Motion: Stationary

Shape: Straight body and tail, tapered head

Length (modified Knott test): 300 to 322 µm

Width: 6.7 to 7.0 µm

Microfilariae of D. immitis (bottom) and A. reconditum (top) as they appear in a modified Knott test. In these preparations, the microfilariae of D. immitis have a greater length and are wider at midbody than those of A. reconditum (see table above).

Radiography

• 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.

• It is important to note that although some radiographic changes can be highly supportive of heartworm disease, particularly in the advanced stages, radiographs should always be combined with other diagnostic test results before assuming a definitive diagnosis.

Chest radiograph

Control and Prevention

• Heartworm infection is prevented by the administration of macrocyclic lactone preventives as soon as possible, and by behaviorally limiting contact with mosquitoes. Use of products on dogs that repel mosquitoes, further reduces risk of heartworm infection.
• Heartworm 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 oral ivermectin, oral milbemycin oxime, oral, topical or injectable moxidectin, and topical selamectin (Visit CAPC’s Quick Product Reference Guide).
• RESISTANCE - Some heartworm isolates can develop to adults even in dogs receiving routine prophylaxis with any of the available macrocyclic lactones. However, efficacies against resistant heartworms may vary among available products and formulations.
  • Infected dogs must be treated promptly with an approved adulticide (see below) and non-infected dogs should be maintained on macrolide preventives year round to protect them from heartworm disease.
  • Annual antigen testing of dogs receiving preventives is important. Annual testing will ensure that infected dogs are identified and treated as soon as possible. For dogs living in high endemic areas, twice-a-year testing may be advised.
  • At this time, the geographic extent of these resistant heartworms is not known. Re-location of re-homed and rescued dogs that are not treated to removed adult heartworms and microfilariae increases the potential risk and rate of spread.

• The more common heartworm preventives for dogs include:
  • Advantage Multi® Topical Solution for Dogs (imidacloprid/moxidectin) (Elanco)
  • HEARTGARD® Plus Chewables for Dogs (ivermectin/pyrantel) (Boehringer Ingelheim)
  • Imectro^TM Chew (ivermectin, pyrantel pamoate and praziquantel) (Ceva)
  • Interceptor® Flavor Tabs® for Dogs & Cats (milbemycin oxime) (Elanco)
    
  • Interceptor^TM Plus (milbemycin oxime/praziquantel) (Elanco)
  • Iverhart Max® Chewable Tablets (ivermectin/pyrantel pamoate/praziquantel)  (Virbac)
  • Iverhart Plus® Flavored Chewables (ivermectin/pyrantel) (Virbac)
  • MilbeGuard® (milbemycin oxime) (CEVA)
  • ProHeart® 6 (moxidectin) (Zoetis)
    
  • ProHeart® 12 (moxidectin) (Zoetis)
  • Revolution® (selamectin) (Zoetis)
    
  • Sentinel® Flavor Tabs® (milbemycin oxime/lufenuron) (Merck Animal Health)
  • Sentinel® Spectrum® Chewables (milbemycin oxime/lufenuron/praziquantel) (Merck Animal Health)
  • Simparica Trio^TM (sarolaner, moxidectin, pyrantel pamoate) (Zoetis)
  • Trifexis® (milbemycin oxime/spinosad) (Elanco)
  • Tri-Heart® Plus Chewable Tablets (ivermectin/pyrantel) (Merck Animal Health)

Treatment

The goals of treatment are to address the clinical condition of the animal and to eliminate adult heartworms, and microfilariae.

• Any or all of the following may be medically indicated to stabilize dogs presenting with clinical heartworm disease:
  • corticosteroid therapy
  • fluid therapy
  • diuretics
  • vasodilators
  • positive inotropic agents
• Dogs receiving a macrocyclic lactone should be maintained on preventive. If a dog is not receiving a macrocyclic lactone preventive, administration of preventive should be initiated as soon as any severe medical condition is stabilized.  The purpose of preventive use is to eliminate new larvae. Treatment with adulticide (melarsomine; see below) is for removal of adult worms and will not kill newly introduced larvae. Melarsomine dihydrochloride is an organo-arsenical adulticide that is available as an injectable product in two branded products (Immiticide (Boehringer Ingelheim); Diroban (Zoetis).
• CAPC recommends treating infected dogs with adulticide as soon as is medically practical.  Delaying treatment while maintaining dogs on preventives may promote progression of disease.
• Infected dogs may be placed by veterinarians into one of three disease 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 AND INCREASED SAFETY IN DOGS WITH EVIDENCE OF HIGH WORM BURDENS AND/OR SEVERE DISEASE OBSERVED WITH THE 3-INJECTION REGIMEN MAKES THIS APPROACH THE TREATMENT OF CHOICE FOR ALL HEARTWORM INFECTED DOGS. There is opinion that melarsomine is not effective against heartworms younger than 4 months of age. Because infected mosquitoes can continue to transmit heartworm over a period of many months, heartworms of different ages can be present in dogs. To address this, many veterinarians have also adopted a delay strategy involving a combination of doxycycline and preventive. Both are administered for 1 month followed by an additional month of prevention prior to administration of the first dose of melarsomine. The 3-injection protocol is then followed as discussed above. This strategy is thought to address the gaps discussed above between prevention and adulticide. However, there is alternative opinion that the delay can be reduced to 1 month without any compromise in efficacy (see Carretón et al, 2019 in the reference section). Other, off-label regimens for administration of melarsomine dihydrochloride are not recommended.
  • Melarsomine treatment may not be completely efficacious in all situations. This may necessitate additional therapy or alternate therapeutic strategies (see below).
  • All melarsomine-treated dogs should be antigen tested 6-7 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. However, recent research using a combination of topical moxidectin and doxycycline resulted in demonstrable efficacy. The combination regimen also will reduce or eliminate microfilariae. This decreases risks and concerns about resistance selection.
  • False-negative antigen test results have been observed for dogs treated with slow-kill protocols, presumably because of antigen-antibody complex formation. Consequently, antigen test results from dogs on slow-kill may not be a reliable indicator of infection status.
  • Although the “slow-kill” method is not the preferred heartworm treatment, if it is the only medically acceptable option, microfilariae should be eliminated as soon as possible, and dogs should be maintained on a mosquito repellent as discussed above.
  • Topical moxidectin/imidacloprid is label approved in dogs for removal of microfliariae when used monthly.
• Post-adulticide microfilaricidal treatment
  • If microfilariae are present after treatment, they should be cleared from the circulation. Caution should be applied when treating dogs with high numbers of microfilariae. Rare anaphylaxis-like reactions have occurred a very few dogs. Microfilariae produced by certain heartworm isolates can persist for more than a year in the presence of high levels of some macrocyclic lactones., These microfilariae put other dogs at risk of infection (or re-infection). Veterinarians who experience difficulties removing microfilariae should consult a parasitologist or other heartworm specialist for advice.
• Wolbachia pipientis
  • Many filarial nematodes, including D. immitis, harbor obligate, intracellular, gram-negative bacteria known as Wolbachia pipientis. The use doxycycline in regimens discussed above is intended to eliminate these co-habitant organisms.
  • Although research continues, current data indicate that treatment of dogs with doxycycline prior to adulticide therapy to eliminate Wolbachia will i)improve adulticidal and microfilaricidal efficacy ii) reduce the gross pulmonary pathologic changes that occurs as a result of dead and dying worms and fragments, , and iii) interfere with the ability of the microfilariae to develop into infective larvae in mosquito vectors.

Public Health Considerations

• More than 100 human cases of pulmonary dirofilariasis have been reported in the United States in the last fifty years. Most cases occur in regions where heartworm is common in dogs (see Lee et al, 2010 in the reference section).
• 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), 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 transmission of D. immitis to people.

Selected References

• Bowman DD, Atkins CE. 2009. Heartworm biology, treatment, and control. Vet Clin North Am Small Anim Pract. 39(6):1127-58

• Carretón E, Falcón-Cordón Y, Falcón-Cordón S, Marchón R, Maton JI, Montoya-Alonso JA. 2019. Variation of the adulticide protocol for the treatment of canine heartworm infection: Can it be shorter? Vet Parasitol. 272:54-56.
• Drake J, Parrish RS. 2019. Dog importation and changes in heartworm prevalence in Colorado 2013-2017. Parasites and Vectors 12:207.
• Gruntmeir J, Long M, Blagburn B, Walden H. 2019. Heat Treatment: Improved Detection of Male Only Dirofilaria immitis Infection and Overall Assessment of Antigen Detection in Necropsy Positive and Negative Sheltered Dogs in Florida, USA. Proceedings of the 16^th Triennial Symposium American Heartworm Society, September 8-11, 2019, New Orleans, LA
• 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.
• Ledesma N, Harrington L. 2011. Mosquito vectors of dog heartworm in the United States: Vector status and factors influencing transmission efficiency. Topics in Comp Anim Med 26(4):178-185.
• 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.
• McCall JM, Hodgkins E, Varloud M, Mansour A, DiCosty U. 2017. Blocking the transmission of heartworm (Dirofilaria immitis) to mosquitoes (Aedes aegypti) by weekly exposure for one month to microfilaremic dogs treated once topically with dinotefuran-permethrin-pyriproxyfen. Parasites and Vectors 10 (Suppl 2):511:88-95.
• McCall JM, Varloud M, Hodgkins E, Mansour A, DiCosty U, McCall S, Carmichael J, Carson B, Carter J. 2017. Shifting the paradijm in Dirofilaria immitis prevention: blocking transmission from mosquitoes to dogs using repellents/insecticides and macrocyclic lactone prevention as part of a multimodal approach. Parasites and Vectors 10 (Suppl 2):525):75-85.
• Paterson T, Fernandez C, Burnett P, Lessey L, Hockley T, Schaper R. Heartworm Control in Grenada, West Indies: Results of a field study using imidacloprid 10% + moxidectin 2.5% (Advantage Multi®, Advocate®) spot-on and doxycycline for naturally acquired Dirofilaria immitis infections. Proceedings of the 27^th Conference of the World Association for the Advancement of Veterinary Parasitology/64^th American Association of Veterinary Parasitologists Annual Meeting, 7-11 July, 2019, Madison, WI, USA, Abstract OA06.08
• Prichard R, Ballesteros C, Geary T, Keller K, Bourguinat C, Pulaski C. 2019. Macrocyclic Lactone Resistance in Dirofilaria immitis: Extent of resistance and investigation of the genomic changes underlying resistance. Proceedings of the 27^th Conference of the World Association for the Advancement of Veterinary Parasitology/64^th American Association of Veterinary Parasitologists Annual Meeting, 7-11 July, 2019, Madison, WI, USA, Abstract OA01.04
• Starkey LA, Bowles JV, Blagburn BL. 2019. Comparison of acid vs. heat treatment for immune complex dissociation and detection of Dirofilaria immitis antigen in canine plasma. Proceedings of the 16^th Triennial Symposium American Heartworm Society, September 8-11, 2019, New Orleans, LA, Pg 47.