I. Heartworm Disease in California

A. Locations

1.  Foothills of the Sierra Nevada--Grass Valley, Placerville

2.  East Sacramento

3.  Santa Cruz mountains

4.  Canyons northwest of Los Angeles (Topanga Canyon)

B. Heartworms not reported in Davis and the majority of Southern California.

II. Diagnosis

A. Both in-house kits and reference labs test for antigen associated with mature female D. immitis. The antigen test is the most sensitive diagnostic method for the detection of heartworm disease. The amount of antigen in circulation bears a direct relationship to the number of mature female worms.

1.  Ratio of females to males is variable so the relationship between the antigen concentration and worm burden is less than perfect.

B. False positive results are usually the result of technical errors. False negative results occur most commonly when infections are light, female worms are immature, only male worms are present, and/or the test kit or sample has not been warmed to room temperature appropriately.

C. Microfilariae testing is complimentary. The current generation of heartworm antigen tests identify most "occult" infections consisting of at least one mature female worm and are nearly 100% specific. Since less than 1% of infections are patent but not antigenemic, testing for antigen will detect more infections than testing for only microfilariae.

1.  It is important to check for microfilariae when a dog tests positive with an antigen test

III. Approach to the Heartworm Positive Dog

A. Radiography provides the most objective method of assessing the severity of heartworm cardiopulmonary disease.

1.  Enlarged, tortuous, truncated intralobar branches of the pulmonary arteries.

2.  Variable degrees of pulmonary parenchymal disease.

3.  Overtime all dogs with heartworm disease will develop right heart enlargement and are at risk for right sided congestive heart failure.

B. Echocardiography is not an efficient diagnostic tool in lightly infected dogs since the worms are usually in the peripheral branches of the pulmonary arteries beyond the echocardiographic field of view. Size of the patient determines whether or not you can find heartworms in the in the main pulmonary artery and proximal branches. The smaller the dog, the harder it is to visualize worms.

C. Pre-adulticide evaluation

1.  Clinical laboratory data including complete blood count and serum biochemistry data should be collected to complement information obtained from physical examination, antigen tests and thoracic radiography.

2.  The most important variables influencing the probability of post-adulticide thromboembolic complications and the outcome of treatment are the extent of concurrent pulmonary vascular disease and the severity of infection.

IV. Melarsomine Dihydrochloride (Immiticide®)

A. Administration

1.  Deep intramuscular injection into the epaxial lumbar muscles to allows for rapid absorption and avoids markedly painful reactions associated with subcutaneous injection.

2.  Associated with mild swelling and some soreness at the injection site for a few days.

3.  Strategies to avoid this complication:

a.  Use correct needle size (gauge and length) and switch to fresh sterile needle after drawing up the drug.

b.  Ensure that the injection is deposited deeply into the musculature.

c.  Hold your finger over the injection site for at least 1-3 minutes once to needle is removed to ensure no drug tracks up into the subcutaneous tissue.

d.  Use proper restraint techniques. Consider sedating excitable/fractious patients (Butorphanol 0.1-0.2mg/kg IV or IM, Buprenorphine 0.0075-0.01mg/kg IV or IM).

B. Standard protocol (2-dose) vs. alternative protocol (3-dose)

1.  3-dose protocol (one injection followed one month later by two injections 24 hours apart) is the choice treatment of the American Heartworm Society and several teaching hospitals regardless of stage of disease.

2.  Increased safety and efficacy (on average kills half the worms each time)--it takes one injection to kill males and at least two injections to kill females.

3.  Exercise restriction should be enforced for at least three weeks after adulticidal treatment.

4.  Unlike Thiacetarsamide, melarsomine is not hepatotoxic; the organ of toxicity is the lung.

C. Acute adverse effects

1.  Pain and swelling at the injection site is common.

a.  Avoid superficial or subcutaneous injection and leakage.

b.  Apply firm pressure to area after injection.

2.  Post-adulticidal pneumonitis--low grade fever, coughing, hemoptysis, exacerbation of right heart failure, depression, lethargy, anorexia (may be due to drug effects or dying worms and pulmonary thromboembolism).

a.  5-15 days post-adulticide treatment is the most common time frame but can see side effects up to 4 weeks after administration.

b.  Standard treatment is strict cage rest, anti-inflammatory doses of glucocorticoids, and supplemental oxygen, if necessary.

c.  Empirical use of aspirin as an antithrombotic or to reduce pulmonary arteritis is no longer recommended.

V. Caval Syndrome (Dirofilarial Hemoglobinuria)

A. Develops acutely when there is a sudden cessation of blood flow, which allows worms to fall back into the right heart.

1.  Sudden onset of severe lethargy and weakness accompanied by hemoglobinemia and hemoglobinuria.

2.  Echocardiographic diagnosis by visualization of the heartworms within the tricuspid orifice.

a.  Heartworms cause tricuspid regurgitation and red cell shearing (lysis) as the cells pass through the tricuspid valve.

3.  Surgical removal of worms from the right atrium and orifice of the tricuspid valve can be accomplished under anesthesia using flexible alligator forceps (Ishihara forceps) or retrieval snare introduced via the jugular vein.

4.  In the weeks following removal surgery adulticidal therapy is recommended to eliminate any remaining worms.

5.  Prognosis--guarded to poor without therapy.

VI. Wolbachia

A. Description

1.  Recently discovered endosymbiont, found in Dirofilaria immitis as well as many insects and arthropods.

2.  Obligate, intracellular, gram-negative bacteria recognized as Wolbachia in heartworms in 1995

3.  In D. immitis Wolbachia are found in the lateral chords of adults and microfilariae. In the female worm they are also found in the oocytes and in all the embryonic stages of microfilaria developing in the uterus.

B. Pathogenesis

1.  Antigenicity of Wolbachia and their products has been implicated in filarial inflammatory responses.

2.  Host (dog) may be exposed to Wolbachia by several routes:

a.  Released when adult worms or larval stages die (host defense reaction or chemotherapy drugs).

b.  Shed by female uterine contents and in microfilariae.

c.  Excretory contents of adult worms.

3.  Host can be continuously exposed to Wolbachia for the duration of the infection and can develop an antibody response to its products. Antibodies are formed in response to exposure to a surface protein (WSP) antigen.

4.  Any Wolbachial product (Wolbachial antigen) can pose a potential problem once it is exposed to the circulatory system--can affect the vasculature of the lungs, kidneys, liver, spleen.

C. Treatment

1.  Organisms are readily cleared with doxycycline. Other reported effective drugs: rifampin, azithromycin. Not effective: chloramphenicol, erythromycin, ciprofloxacin.

2.  Therapy clears microfilaria and sterilizes and stunts growth of adults.

D. Future research

1.  Adulticidal treatment may be enhanced by treating Wolbachia with antibiotics--worms may become more susceptible to melarsomine if weakened by the clearing of Wolbachia.

2.  Wolbachia antigens, whether natural or recombinant, may offer a novel set of compounds with diagnostic applications and can be candidates for vaccine development.

3.  There is one abstract that suggests that a combination of doxycycline and ivermectin kills adult heartworms within 9 months, suggesting that killing Wolbachia makes the heartworm more susceptible to ivermectin.

VII. Use of HWP as Adulticidal Therapy

A. Ivermectin or ivermectin/pyrantel at normal HWP monthly doses is highly effective against late precardiac larvae and young (<7mo post-infection) adult D. immitis.

B. Method requires more than a year of continuous monthly administration and may take 2 or more years before heartworms are eliminated completely.

C. Practitioners may feel this method is safer and less expensive than melarsomine, or clients may request the protocol as an alternative.

D. This "slow-kill" effect has the disadvantage of persistent infection and ongoing damage to the pulmonary vasculature. Exercise has been demonstrated to worsen the tissue damage (radiographs and necropsy findings).

E. The American Heartworm Society does not recommend this protocol as a substitute for adulticide (melarsomine) therapy.

VIII. Macrocyclic Lactone Heartworm Preventatives

A. 2001 survey of more than 18,000 veterinary clinics in the USA identified more than 240,000 dogs and 3,000 cats infected with D. immitis.

1.  Compliance failure--Missing one or more monthly doses during the heartworm transmission season or initiating a monthly heartworm prevention program 2 months or longer after the season starts.

B. Preventatives

1.  Ivermectin, Milbemycin oxime, Moxidectin, and Selamectin.

a.  Anthelmintic activity against: microfilaria, L3, L4, young adult heartworms (L5).

C. Ivermectin (IVM) and Ivermectin/Pyrantel Pamoate (IVM/PP)

1.  Monthly ivermectin for 1 year was 97.7% and 95.1% effective against 3 and 4 month old heartworms respectively.

2.  IVM/PP activity against heartworms was 95% with 29 monthly doses against 7-month-old worms.

3.  The earlier the treatment is started the more stunted are the worms.

4.  The later monthly dosing is started with IVM, the longer worms will survive, the more likely antigen will be detected, the higher the antigen level, and the longer the dog will be antigen positive.

5.  The earlier monthly dosing with IVM is started, the less likely a patent infection will develop, the lower the microfilaria count, and the shorter the patent period.

D. Milbemycin oxime (MBO) (Interceptor, Novartis Animal Health)

1.  Results of several comparative studies have shown that adulticidal activities of monthly administered MBO have not been as effective as IVM--especially against older heartworms.

E. Moxidectin (MOX) (ProHeart 6, Fort Dodge Animal Health)

1.  Oral dose of 0.5ug/kg was highly effective against 2 month old worms.

2.  Moxidectin long-acting injectables have been withdrawn from the market due to excessive fatal complications.

F. Selamectin (SEL) (Revolution, Pfizer Animal Health)

1.  Shown to be 98% effective when given for 1 year against 3-month-old heartworms.

2.  Partial effect on adult heartworms when administered topically at recommended dosages for 18 consecutive months, and many of the surviving worms in treated dogs had abnormal motility/appearance.

References

1.  American Heartworm Society. 2005 Guidelines for the Diagnosis, Prevention and Management of Heartworm Infection in Dogs.

2.  Kittleson MD and Kienle RD. Small Animal Cardiovascular Medicine. 1998.

3.  Kramer L, et al. Is Wolbachia complicating the pathological effects of Dirofilaria immitis infections? Veterinary Parasitology 133 (2005) 133-136.

4.  McCall, JW. The safety-net story about macrocyclic lactone heartworm preventives: A review, update, and recommendations. Vet. Parasitology 133 (2005) 197-206.

5.  Simon et al. Immunopathology of Dirofilaria immitis Infection. Veterinary Research Communications, 31 (2007) 161-171.

6.  Hampshire VA. Evaluation of efficacy of heartworm preventive products at the FDA. Veterinary Parasitology 133 (2005) 191-195.

7.  Veterinary Information Network

8.  Kozek WJ. What is new in the Wolbachia/Dirofilaria interaction? Veterinary Parasitology (2005) 127-132.