The Murmur Newsletter - October 2017

 

By: Sarah Clay Bell, DVM, MS, Diplomate, ACVIM (Cardiology)

 

Environment and Life Cycle

 

Climate change and suburban sprawl have resulted in local environmental changes providing for the expansion of the heartworm vectors and heartworm disease into new areas. Peak months for transmission of Dirofilaria immitis in the Northern Hemisphere are typically July and August when average daily temperatures are well above 57 degrees F. In our region, we may see a temporary increase in the amount of heartworm disease requiring treatment due to many rescue dogs arriving in our area from Hurricanes Harvey and Irma.

 

Dogs serve as the natural definitive host and reservoir for Dirofilaria immitis developing patent infections with adult worms that produce microfilaria thereby facilitating transmission. Cats are rarely microfilaremic and serve only as a limited source of heartworm infection.

 

Prevention

 

 

There are several effective and safe choices for the prevention of heartworms in dogs and cats. Because mosquito vectors are ubiquitous in the environment, all dogs and cats in heartworm endemic areas are at risk of infection. Despite the lack of hospitable temperatures in northern parts of the US,  the American Heartworm Society recommends year round prophylaxis.

 

The heartworm preventatives on the market belong to a class of drug called macrocyclic lactones. These drugs kill microfilariae as well as L3 and L4 larvae. There may also be some effectiveness against adult worms.2, 3 Information on individual therapies is available on the manufacturer websites.

 

• Bayer Advantage Multi ® (moxidectin) is the only macrocyclic lactone preventive product that is FDA approved for treatment of circulating microfilariae.4

 

Loss of efficacy and/or resistance to the preventives on the market is becoming more widespread, particularly in the Mississippi River valley. Loss of efficacy, however, is most commonly explained by failure of the owner to strictly administer preventive as directed.5, 6 Dogs and cats can become infected after one missed dose of heartworm preventive. All available preventive products are highly effective if given routinely; however, there have been reports of truly resistant strains primarily in the Mississippi Delta region.7-9

 

Testing

• Antigen produced by adult female heartworms can be detected as early as 5 months post-infection, however, dogs receiving preventive drugs can have delayed antigenemia up to 9 months post infection. Bedside antigen tests are highly sensitive.6, 10

• Circulating antigen-antibody complexes can block antigen binding sites resulting in false negative tests.11-14

• Microfilaria testing should be performed concurrently with antigen tests, as some antigen negative but infected dogs will have circulating microfilaria. Some infected dogs can be antigen and microfilaria negative, as in infections with immature females, single sex male worms, or low worm burdens.

• If the result obtained on the test does not fit with the clinical picture, confirmation by a reference lab is recommended. Heat fixation of antigen samples from dogs that are microfilaremic can result in disruption of antigen/antibody complexes and facilitate the detection of antigen.11-15 This test is not recommended for every heartworm antigen negative dog, however, if there is high clinical suspicion of heartworm infection based on clinical signs and staging, heat fixation is warranted. Reference laboratories can perform heat fixation on samples sent to their facilities. False positive antigen results are rare, but cross-reaction with Angiostrongylus vasorum and Spirocera lupi antigens has been reported.15

 

 

Heat fixation of samples for antigen detection has also been studied in cats. The recommendation for testing for cats is typically antibody and antigen testing. Cats usually have low worm burdens resulting in most cats testing antigen negative. Cats are also much less likely to be microfilaremic. In a study of 385 shelter and free-roaming cats, heat fixation of samples significantly increased the detection of antigen overall and in cats that were antibody positive.13 Heartworm disease in cats is often an elusive diagnosis, so this is a promising development.

 

 

 

 

 

 

 

Staging

 

 

Once a patient has been diagnosed, further staging of their heartworm disease is indicated. Thoracic radiographs alone or combined with echocardiography are useful to determine prognosis as well as assess risk of complications associated with treatment. Radiographic changes consistent with heartworm infection include dilation, possibly severe, of the caudal lobar pulmonary arteries. In severe cases, right heart enlargement can be seen radiographically. Associated pulmonary parenchymal changes can occur due to inflammatory changes and pulmonary vascular remodeling in response to adult heartworms. Tracheobronchial lymph nodes can also become enlarged secondary to inflammation. Echocardiography can be used to identify heartworms, however, antigen testing is much more sensitive than an echocardiogram for identification.  Dogs infected with low worm burdens may not have identifiable heartworms on echocardiogram as worms may be out of the field of echocardiographic view, deep in the smaller pulmonary arterial branches.16

 

 

 

Primary care veterinarians are at the forefront of diagnosis and treatment of heartworm disease. The veterinary cardiologist can provide a supportive role in staging of severely affected dogs, identifying the presence of caval syndrome, and helping to elucidate concurrent abnormalities that may influence treatment such as the presence of severe pulmonary hypertension or pulmonary thromboembolic disease. Identification of concurrent abnormalities in more severe cases can help identify those at greater risk of complications post-treatment, thus, lowering the risk of said complications. Concurrent syndromes such as pulmonary hypertension or right heart failure can be palliated, improving quality of life and decreasing symptoms of the infected animal but do sadly offer a much more guarded long term prognosis.

 

 

 

 

 

 

 

 

Dogs are classified as mild, moderate, severe, or very severe (classes 1 – 4) based on the presence of clinical, radiographic, and clinicopathologic abnormalities. Patients with severe clinical signs, such as intravascular hemolysis, right heart failure (ascites), and hemodynamic instability may have caval syndrome. Caval syndrome is a life-threatening emergency that occurs in dogs with very high worm burdens, resulting in shearing damage to red blood cells and obstruction to return of blood to the right heart by a large heartworm mass. Treatment is emergency heartworm retrieval. Adulticide treatment should not be administered to these animals. Reported mortality either intra- or immediately post-operatively is up to 28%. Once recovered from surgical extraction of the bulk of worms, remaining infection should be addressed with melarsomine. For dogs that survive to discharge, long term survival can be good.18

 

 

Dogs that have symptoms (cough, exercise intolerance) but do not have caval syndrome should be stabilized prior to undergoing adulticide treatment. Anti-inflammatory doses of steroids can provide significant relief of respiratory signs. All dogs that are diagnosed with heartworm disease should be severely activity restricted by their owners as exercise results in increased pulmonary blood flow to a damaged vascular bed which may cause worsening of clinical signs and pulmonary pathology. Post-treatment activity restriction is paramount in improving outcome and lessening the risk of PTE.

 

Treatment

 

 

Our treatment recommendations reflect those of the American Heartworm Society.

• Melarsomine is the only drug approved by the FDA for treatment of adult heartworm society. Melarsomine dihydrochloride is manufactured by Merial and is marketed as Immiticide®. The FDA recently approved Zoetis to manufacture a generic version of melarsomine (Diroban®). Melarsomine only has efficacy against worms older than 4 months. The American Heartworm Society advocates the use of a split three-dose protocol for all cases. The first dose is administered, and a month later two more doses are given 24 hours apart. The advantage of this three-dose protocol is increased safety and efficacy of treatment. “Slow kill” treatment with doxycycline and a macrocyclic lactone is not recommended. These protocols (typically ivermectin and doxycycline) result in death of the adult worms over a period of approximately 2 years, during which time damage to the pulmonary arteries and pulmonary parenchyma by the parasites is ongoing. For complete treatment recommendations, please consult the American Heartworm Society guidelines.

• Concurrent use of doxycycline serves to kill the symbiotic bacteria of Dirofilaria immitis. Doxycycline can kill L3 and L4 heartworm larvae and can suppress microfilaremia.2, 17 Dogs pre-treated with a macrocyclic lactone and doxycycline prior to melarsomine have less pulmonary pathology on necropsy than untreated dogs.1

• Pre-treatment for two months with a macrocyclic lactone can help close the gap between the effectiveness of melarsomine and that of the macrocyclic lactone with respect to stage of heartworm eliminated. As microfilariae die, the rapid decrease in number can incite an inflammatory response. In field studies, moxidectin administered topically was associated with no adverse effects and a topical preparation is FDA approved for treatment in microfilaremic dogs.3

• If arsenicals (melarsomine) are contraindicated either due to intolerance, instability, previous reaction, or is not possible due to shortage or finances, monthly use of topical moxidectin combined with doxycycline has shown promise as an effective “slow kill” combination. Studies are ongoing, but have shown promise and result in a kill rate that is much faster than that reported with ivermectin/doxycycline in combination. Preliminary data from a clinical study indicate efficacy rates approaching 95%, minimal side effect profile, and lack of antigenemia past 210 days post infection.  An experimental study is ongoing that will determine percent efficacy based on retrieval of heartworms at post-mortem.

• There remains no recommended adulticide treatment for heartworm disease in cats, but a confident diagnosis of heartworm disease with improved antigen detection may aid in treatment of associated clinical signs and monitoring on the part of the owner for the development of clinical signs.

As heartworms die, there is an inevitable risk for PTE. Dead and dying worms incite an inflammatory response and activate platelets as well as causing physical obstruction of distal pulmonary arterioles. Strict activity restriction decreases risk of PTE and is recommended for approximately 6 - 8 weeks following the last injection of melarsomine.

 

As dogs from hurricanes Harvey and Irma are relocating into our regions, the risk of heartworm transmission to other dogs in the area will increase. Monthly prophylaxis remains key to prevention. If a treatment lapse occurs, dogs should be tested 6 months following a lapse in prevention. Since some dogs on treatment will develop antigen-antibody complexes, if the patient’s clinical picture does not fit with the results of the antigen testing, consider heat fixation of the sample to unmask antigenemia. At CVCA we are always happy to help with any of your complicated heartworm cases or those that are proving challenging from a diagnostic perspective.

Works Cited Sections for “Heartworm Disease: A Review”

 

1. Current Canine Guidelines for the Prevention, Diagnosis and Management of Heartworm (Dirofilaria immitis) Infection in Dogs. 2014.

2. Chandrashekar R, Beall MJ, Saucier J, O'Connor T, McCall JW and McCall SD. Experimental Dirofilaria immitis infection in dogs: effects of doxycycline and Advantage Multi(R) administration on immature adult parasites. Veterinary parasitology. 2014;206:93-8.

3. McCall JW, Arther R, Davis W and Settje T. Safety and efficacy of 10% imidacloprid+2.5% moxidectin for the treatment of Dirofilaria immitis circulating microfilariae in experimentally infected dogs. Veterinary parasitology. 2014;206:86-92.

4. Bowman DD, Charles SD, Arther RG and Settje T. Laboratory Evaluation of the Efficacy of 10 % Imidacloprid + 2.5 % Moxidectin Topical Solution (Advantage(R) Multi, Advocate(R)) for the Treatment of Dirofilaria immitis Circulating Microfilariae in Dogs. Parasitology research. 2015;114 Suppl 1:S165-74.

5. Atkins CE, Murray MJ, Olavessen LJ, Burton KW, Marshall JW and Brooks CC. Heartworm 'lack of effectiveness' claims in the Mississippi delta: computerized analysis of owner compliance--2004-2011. Veterinary parasitology. 2014;206:106-13.

6. Rohrbach BW and Patton S. Effects of diagnostic test accuracy and treatment efficacy on the occurrence of suspected failure of heartworm prophylaxis in dogs. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine. 2013;27:791-7.

7. Bourguinat C, Lee AC, Lizundia R, Blagburn BL, Liotta JL, Kraus MS, Keller K, Epe C, Letourneau L, Kleinman CL, Paterson T, Gomez EC, Montoya-Alonso JA, Smith H, Bhan A, Peregrine AS, Carmichael J, Drake J, Schenker R, Kaminsky R, Bowman DD, Geary TG and Prichard RK. Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance. Veterinary parasitology. 2015;210:167-78.

8. Pulaski CN, Malone JB, Bourguinat C, Prichard R, Geary T, Ward D, Klei TR, Guidry T, Smith G, Delcambre B, Bova J, Pepping J, Carmichael J, Schenker R and Pariaut R. Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. Parasites & vectors. 2014;7:494.

9. Blagburn BL, Arther RG, Dillon AR, Butler JM, Bowles JV, von Simson C and Zolynas R. Efficacy of four commercially available heartworm preventive products against the JYD-34 laboratory strain of Dirofilaria immitis. Parasites & vectors. 2016;9:191.

10. Atkins CE. Comparison of results of three commercial heartworm antigen test kits in dogs with low heartworm burdens. Journal of the American Veterinary Medical Association. 2003;222:1221-3.

11. Drake J, Gruntmeir J, Merritt H, Allen L and Little SE. False negative antigen tests in dogs infected with heartworm and placed on macrocyclic lactone preventives. Parasites & vectors. 2015;8:68.

12. Velasquez L, Blagburn BL, Duncan-Decoq R, Johnson EM, Allen KE, Meinkoth J, Gruntmeir J and Little SE. Increased prevalence of Dirofilaria immitis antigen in canine samples after heat treatment. Veterinary parasitology. 2014;206:67-70.

13. Little SE, Raymond MR, Thomas JE, Gruntmeir J, Hostetler JA, Meinkoth JH and Blagburn BL. Heat treatment prior to testing allows detection of antigen of Dirofilaria immitis in feline serum. Parasites & vectors. 2014;7:1.

14. Little SE, Munzing C, Heise SR, Allen KE, Starkey LA, Johnson EM, Meinkoth J and Reichard MV. Pre-treatment with heat facilitates detection of antigen of Dirofilaria immitis in canine samples. Veterinary parasitology. 2014;203:250-2.

15. Aroch I, Rojas A, Slon P, Lavy E, Segev G and Baneth G. Serological cross-reactivity of three commercial in-house immunoassays for detection of Dirofilaria immitis antigens with Spirocerca lupi in dogs with benign esophageal spirocercosis. Veterinary parasitology. 2015;211:303-5.

16. Miller MWaG, Sonya G. Canine Heartworm Disease. Kirk's Current Veterinary Therapy XIV. 2009;1:837 - 842.

17. McCall JW, Kramer L, Genchi C, Guerrero J, Dzimianski MT, Mansour A, McCall SD and Carson B. Effects of doxycycline on heartworm embryogenesis, transmission, circulating microfilaria, and adult worms in microfilaremic dogs. Veterinary parasitology. 2014;206:5-13.

18. Bove CM, Gordon SG, Saunders AB, Miller MW, Roland RM, Achen SE, Drourr LT and Boggess MM. Outcome of minimally invasive surgical treatment of heartworm caval syndrome in dogs: 42 cases (1999-2007). Journal of the American Veterinary Medical Association. 2010;236:187-92.

 

 

 

 

    

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