|
|||||||||||||||||||||||||||||||||||
Antidepressants |
Antimicrobial Agents |
Opioids |
Cardiac Drugs |
Immunosuppressants |
Miscellaneous |
(Source: http://www.vetmed.wsu.edu/depts-vcpl/drugs.aspx)
Oral administration: Ivermectin and milbemycin oxime are available for monthly oral administration. Some of these formulations are flavored and chewable to increase patient acceptance and facilitate administration. Dose units are packaged for dogs within prescribed weight ranges. To be maximally effective, heartworm prophylaxis should be given year-round, but if seasonal treatment is chosen, administration should begin within one month of the anticipated start of transmission and should continue for at least 3 months after transmission ceases.
Topical administration: Moxidectin and selamectin are available as a topically applied liquid. The parameters for treatment with topical products are the same as for monthly oral chemoprophylaxis.
Parenteral administration: A single dose of the slow-release (SR) formulation of subcutaneously injected moxidectin-impregnated lipid microspheres provides continuous protection for 6 months. Treatment every 6 months is recommended for maximal protection.
Reports of Lack of Efficacy
Lack of efficacy (LOE) of a heartworm preventive product is considered by the Center for Veterinary Medicine of the Food and Drug Administration (FDA) in the United States as a dog testing heartworm positive regardless of appropriateness of dosage or administration consistency. There are many possible reasons for reports of LOE, including failure to administer sufficient preventive, failure to administer the preventive when it should be given, failure of a dog to retain a dose, and failure of absorption of active ingredient. There is also biological variation in how hosts within the same species metabolize a drug and host immune response to parasites, as well as how parasites respond to a drug. Thus, the cause of a reported LOE of a product can be extremely difficult to determine.
Most LOE claims are explained by compliance issues, either between the clinic and the client or the client and the pet. It is possible for an animal to become infected by missing or delayed administration of just one dose of a heartworm preventive product. The likelihood of this occurring is increased in highly endemic areas. Such areas typically have warm temperatures most of the year, an abundance of standing water, and substantial mosquito populations. These endemic areas also have large populations of infected dogs and wild canids available as a reservoir of infection. In addition, manufacturers have improved the sensitivity of heartworm antigen tests during the past decade and more animals with low female worm burdens are now being detected.
The increase in the number of LOE reports to the FDA during the past several years has led to concerns of possible heartworm resistance to the current heartworm preventives. When considering the possibility of resistance, it is generally accepted that genetic polymorphism has always existed in populations of heartworms and resistance-contributing alleles on a gene or multiple genes likely exist that could lead to a decrease or loss of susceptibility to macrocyclic lactones. What is not known is the frequency of these resistant contributing alleles, the number of genes involved, and whether these alleles are dominant or recessive in expressing the resistant phenotype. The phenomenon of developing resistance in a population is much more complex than merely the presence of resistant alleles in individuals. Other factors to consider are the distinct biology of the parasite, the extent of refugia, the relative fitness of the wild-type (susceptible) and resistant genotypes in the absence and presence of macrocyclic lactones, number of animals treated, and the drug dosage used. Product use under specific conditions might select for worms with resistant genes and these surviving worms might develop to become a resistant sub-population.
In vitro assays claim to have identified microfilariae that are less susceptible to high doses of all the macrocyclic lactones. These microfilariae exhibit an allele on the P-glycoprotein gene that differs from the general population. Subsequent in vitro larval migration inhibition assays (LMIA) utilizing L3 derived from these same isolates of microfilariae have demonstrated no significant difference in susceptibility of these propagated isolates as compared with known susceptible isolates. This suggests that either the LMIA is measuring a phenotype that is not associated with resistance, the isolates tested from these prophylaxis failures are not resistant, or other unknown factors are involved.
There are several published studies that examine the susceptibility of the MP3 isolate (also referred to as the MP3 strain ) that was originally collected in northeast Georgia to various heartworm preventives. One study compared the efficacy of a single oral dose of ivermectin and milbemycin at standard prophylactic doses following an experimental infection with 50 L3 in groups of 14 purpose-bred laboratory dogs. A single worm was recovered in both the ivermectin and milbemycin treated groups out of a possible 700 L3. A second study compared the efficacy of a single oral dose of ivermectin and milbemycin, and topical dose of moxidectin and selamectin again at standard prophylactic doses following an experimental infection with 100 L3 in groups of 8 dogs. In this second study, 7 of 8 dogs had 23 to 24 worms out of a possible 800 L3 recovered from the ivermectin, milbemycin, and selamectin groups. No worms were recovered from the moxidectin group. A third study utilizing the MP3 isolate tested three monthly doses of milbemycin after experimental infection with 40 L3 in 10 dogs. No worms were recovered in any of these 10 dogs. Looking at these three studies collectively it was evident the MP3 isolate had decreased susceptibility to single monthly doses of ivermectin, milbemycin, and selamectin but was susceptible to three consecutive monthly doses of milbemycin and a single dose of topical moxidectin. Of greater interest was the 20-fold increase in number of worms recovered when the number of L3 injected was doubled. This would lead one to hypothesize that challenge rates could be involved in LOE and the problems seen in the Mississippi River Valley (MRV) are multi-factorial. Genetically, the MP3 isolate does not exhibit the same allele on the P-glycoprotein gene that was noted in the field isolates from the MRV, whose microfilariae had decreased susceptibility to macrocyclic lactones, suggesting it should be susceptible to preventives.
Another possible factor in LOE is the host–parasite relationship. The exact mode of action of the macrocyclic lactones at preventive doses is not fully known. A study involving Brugia malayi, a filarial nematode causing lymphatic filariasis in humans, indicates ivermectin disrupts the ability of the parasite to secrete a protein from the secretory vesicle, which allows the microfilariae to evade the host immune response. This finding suggests that macrocyclic lactones might work in conjunction with the host immune system to eliminate the microfilaria of Brugia. It is likely the mode of action of macrocylic lactones is similar in Dirofilaria immitis, as heartworm larvae also have a secretory vesicle, but additional studies will need to be conducted before any conclusions can be drawn.
Professional and client education are perhaps the most important factors to consider in addressing the reports of apparent lack of efficacy of preventive products. One must consider all the current research when making decisions on heartworm preventive protocols. Research is ongoing to determine the reason for the increase of LOE in the MRV. Every new study adds to our knowledge base and increases our understanding but also initiates new questions. The complex biology of the parasite, the effect of changing environmental conditions that affect vector populations, the dynamics of host (wild and domestic) populations, and even the dynamics of human interactions with their pets are also relevant. In the face of the many variable factors, it is critical that all members of the veterinary practice ensure that their clients understand the implications of heartworm infection, the risk of heartworm infection in their area, and are providing their pets with appropriate year-round heartworm prevention. The macrocyclic lactones continue to be the best and only option for preventing heartworm infections and efforts need to be intensified in increasing the number of dogs receiving chemoprophylaxis and reminder systems implemented to assist pet owners in purchasing and administering products in a timely manner.
The term strain is being used to describe populations of worms being maintained in laboratories. More appropriately, these populations should be described as propagated isolates. These populations consist of numerous male and female worms, each with unique genetic makeup, undergoing sexual reproduction leading to production of offspring with their own unique genetic design. Strains more appropriately describe the result of asexually derived populations, such as bacteria.
TESTING CONSIDERATIONS: ANNUAL TESTING AND RETESTING
Annual testing is an integral part of ensuring that prophylaxis is achieved and that more timely treatment can be provided to dogs that test positive in order to minimize pathology.
Testing Considerations Following
Noncompliance and When Changing Products
In instances of noncompliance or changing the brand or
type of heartworm preventive, it is important to first ensure
that the dog is free of heartworm infection. The dog should be
tested prior to starting or changing products. A positive test at
this time indicates earlier infection. Typically, most practitioners
retest at six months to coincide with refilling prescriptions and
performing semiannual exams. A positive antigen test at this
time is most likely due to an infection acquired before starting or
resuming preventive therapy; however, in rare instances, existing
infection may be missed (i.e., false negative test due mainly to
young- or low-worm-burden infection). Therefore, subsequent
antigen testing should be performed on the one-year anniversary
date of the initial test and annually thereafter.
If a practitioner wants to more precisely determine if a dog is infected when starting, resuming, or changing any preventive therapy, testing can be performed at this time and again four months later. When one considers that an antigen test may be positive as early as five months after infection and most dogs are positive by nine months after infection, a positive antigen test before dosing is started (or resumed) and/or four months later clearly indicates that the dog was infected prior to initiating (or resuming) dosing or changing products. However, it is important to note that a negative antigen test at four months is highly supportive but does not ensure that a dog was negative for heartworms at the time of starting, resuming or changing any preventive therapy. To minimize the potential for a false-negative test at four months, a second antigen test can be performed one to five months later. A positive antigen test at this later time cannot be unequivocally attributed to earlier or later infection; however, the earlier in this five-month period the test is positive, the more likely infection was acquired prior to initiating (or resuming) dosing or changing products.
Testing of Dogs on Macrocyclic Lactone Preventives
Consistent macrocyclic lactone (ivermectin, milbemycin
oxime, moxidectin or selamectin) chemoprophylaxis will
eventually clear microfilariae from the blood of most dogs with
patent infections. This is achieved by the drugs’ ability to exert a
direct or indirect microfilaricidal effect, depending on the specific
product used, and retard repopulation by gradually suppressing
embryogenesis. Consistent monthly dosing of dogs with patent infections will usually eliminate
microfilariae within six to 12 months of oral dosing with monthly
macrocyclic lactones or one month following moxidectin SR
injection. In the event a pre-existing prepatent infection matures
after starting macrocyclic lactone chemoprophylaxis, microfilariae
are unlikely to be found, or appear only transiently in small
numbers. Since macrocyclic lactone chemoprophylaxis may
negate microfilaria testing and microfilariae do not contribute
to heartworm antigenemia, antigen testing is the most reliable
method of retesting.
OTHER DIAGNOSTIC AIDS
Additional testing methods are useful for confirming the diagnosis and staging the severity of heartworm disease.
Radiography
Assessment of cardiopulmonary status may be useful for evaluating a patient’s prognosis. Radiography provides the most objective method of assessing the severity of heartworm cardiopulmonary disease secondary to heartworm infection. Typical (nearly pathognomonic) signs of heartworm vascular disease are enlarged, tortuous, and often truncated peripheral intralobar and interlobar branches of the pulmonary arteries, particularly in the diaphragmatic (caudal) lobes (Figure 3). These findings are accompanied by variable degrees of pulmonary parenchymal disease. The earliest and most subtle pulmonary arterial changes are most commonly found in the dorsal caudal wedge of the diaphragmatic lung lobes. As the severity of infection and chronicity of disease progress, the pulmonary arterial signs are seen in successively larger branches (Figure 4). In the worst cases, eventually the right heart enlarges.
Figure 3. Moderate heartworm disease. Radiographic images courtesy of Tom Nelson, DVM.
Figure 4. Severe heartworm disease. Radiographic images courtesy of Tom Nelson, DVM.
Echocardiography
The body wall of adult heartworms is highly echogenic and produces distinctive, short parallel-sided images with the appearance of “equal signs” where the imaging plane cuts across loops of the parasite. Echocardiography can provide definitive evidence of heartworm infection, as well as allow for assessment of cardiac anatomic and functional consequences of the disease (Figure 5). However, it is not an efficient method of making this diagnosis, particularly in lightly infected dogs, since the worms often are limited to the peripheral branches of the pulmonary arteries beyond the echocardiographic field of view. When heartworms are numerous, they are more likely to be present in the main pulmonary artery, right and proximal left interlobar branches, or within the right side of the heart where they can be imaged easily. In dogs with hemoglobinuria, visualization of heartworms in the orifice of the tricuspid valve provides conclusive confirmation of caval syndrome.
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Figure 5. Echocardiogram image courtesy of Matt Miller, DVM.
PREADULTICIDE EVALUATION
The extent of diagnostic testing necessary in the pre-adulticide evaluation will vary depending on the clinical status of each patient. Selected clinical and laboratory tests should only be performed to complement information obtained from a thorough history, physical examination, and antigen and microfilaria tests. It is important to note that some key factors influencing the probability of post-adulticide thromboembolic complication and outcome of treatment are not easily measured with standard diagnostic procedures, including 1) the activity level of the dog, 2) the extent of concurrent pulmonary vascular disease, and 3) the severity of infection (high vs. low worm burdens).
High activity levels of the dog are one of the most significant factors contributing to post-adulticidal complications. Prior to treatment, the owner’s ability and willingness to properly confine treated dogs should be thoroughly investigated. Restricting activity is imperative as exercise, excitement, and overheating are harbingers of complications.
Thoracic radiographs can assist in providing an assessment of the animal’s cardiopulmonary status and can be helpful in evaluating the potential for post-adulticide treatment complications. Thromboembolic disease is commonly seen in infected dogs exhibiting radiographic signs of severe pulmonary arterial obstruction, especially in those animals presenting with clinical symptoms. Regardless of radiographic findings, heartworms must be eliminated.
The greater the number of heartworms killed during an adulticide treatment, the more significant the potential for obstructive and inflammatory pathology. Unfortunately, no test (or combination of tests) is available to accurately determine the number of heartworms present. Whether carrying low or high worm burdens, infected dogs can be clinically asymptomatic and have minimal radiographic changes. So, even when performing extensive diagnostics, predicting post-adulticide complications is difficult, if not impossible. One must always assume post-treatment complications are likely and every infected pet must be managed as though a substantial heartworm mass is present.
Historically, due to limitations of some pet owners and animal shelters, large numbers of adulticide treatments have been successfully performed without the benefit of extensive diagnostics. While diagnostics can be an important part of defining an individual’s heartworm disease status, each plan must be developed considering both the animal and individual pet owner. No set protocol has been established for pre-treatment workup and reasonable judgment should always be used to weigh the necessity, benefit, and extent of each diagnostic procedure performed.
Adult heartworms are a graverisk to our canine patients. The longer they remain in an animal, the greater the damage to the cardiopulmonary system and the greater the risk of illness and death. It is probable that treating in the absence of diagnostics, while not ideal, is better than refusing to perform a needed treatment.
PRINCIPLES OF TREATMENT
Successfully treating heartworm disease in asymptomatic patients or those exhibiting signs of mild disease usually is straightforward, but occasionally can be demanding. Those with moderate or severe heartworm disease (Table 2) or patients with concurrent disease are especially challenging.
Table 2. Summary of Clinical Signs of Canine Heartworm Disease
Mild |
Asymptomatic or cough |
Moderate |
Cough, exercise intolerance, abnormal lung sounds |
Severe |
Cough, exercise intolerance, dyspnea, abnormal heart and lung sounds, enlarged liver (hepatomegaly), syncope (temporary loss of consciousness from reduced blood flow to the brain, ascites (fluid accumulation in the abdominal cavity), death |
Caval Syndrome |
Sudden onset of severe lethargy and weakness accompanied by hemoglobinemia and hemoglobinuria |
The goals of any heartworm treatment are to improve the clinical condition of the animal and to eliminate all life stages of the heartworms (microfilariae, larval stages, juveniles and adults) with minimal post-treatment complications. Dogs exhibiting significant clinical signs of heartworm disease should be normalized as much as possible before administering an adulticide. This may require administration of glucocorticosteroids, diuretics, vasodilators, positive inotropic agents, and fluid therapy.
A thorough understanding of the host–parasite relationship is necessary to effectively manage all cases. As expected, the number of worms has an effect on the severity of disease but of equal, if not greater, importance is the activity level of the dog. Controlled studies have shown that dogs infected by surgical transplantation with 50 heartworms and exercise-restricted took longer to develop clinical disease and developed less pulmonary vascular resistance than dogs with 14 heartworms that were allowed moderate activity. This was also evident in naturally infected dogs where there was no correlation between the number of heartworms and pulmonary vascular resistance and is an indication that the host–parasite interaction plays a significant role in the severity of disease. A subsequent study reported similar findings in dogs being treated with melarsomine.
Whereas live heartworms can cause endarteritis and muscular hypertrophy of arteriole walls primarily of the caudal pulmonary arteries, dying and dead heartworms cause a significant portion of pathology seen in clinical disease. As worms die from either natural causes or as a result of administration of adulticidal drugs, they decompose and worm fragments lodge in the distal pulmonary arteriole and capillary beds in the caudal lung lobes blocking blood flow. These worm fragments along with the elicited inflammation and platelet aggregation result in thromboembolisms. During periods of increased activity or exercise, the increased blood flow to these blocked vessels can cause capillary delamination, rupture, and subsequent fibrosis. This leads to increased pulmonary vascular resistance and potential right-sided heart failure. This illustrates a direct correlation between the activity level of the dog and the severity of disease.
ADULTICIDE THERAPY
Melarsomine Dihydrochloride
Melarsomine, administered via deep intramuscular injection into the belly of the epaxial lumbar muscles is the only adulticidal drug approved by the FDA for heartworm treatment. Mild swelling and some soreness at the injection site may be present for a few days, but this can be minimized by ensuring that the injection is deposited deeply with a needle of appropriate length and gauge for the size of dog and body condition. Strictly adhering to the manufacturer’s instructions for administration is imperative. Exercise restriction during the recovery period is ESSENTIAL for minimizing cardiopulmonary complications (see Pulmonary Thromboembolism).
Melarsomine had not been shown to have activity against worms less than 4 months old. New unpublished data suggests that melarsomine may have greater efficacy against juvenile worms than previously believed. The two-injection protocol (i.e., two injections of 2.5 mg/kg body weight 24 hours apart) listed on the product insert for treating class 1 and 2 heartworm disease kills only about 90% of the adult worms. The three-dose alternate protocol (one injection of 2.5 mg/kg body weight followed at least 1 month later by two injections of the same dose 24 hours apart) listed for treating class 3 heartworm disease kills 98% of the worms. These overall efficacy values reflect the percentage of worms killed in groups of dogs and not the percentage of dogs cleared of worms, which are considerably lower than these overall efficacy values.
Staging of the disease and use of the two-dose protocol has failed to adequately ensure treatment success. Therefore, regardless of the severity of the disease (with the exception of caval syndrome), the three-dose protocol is recommended by the American Heartworm Society due to the increased safety and efficacy.
ADJUNCT THERAPY
Macrocyclic Lactones
It is highly probable that a heartworm-positive dog harbors heartworms from less than 1 month to as much as 7 years old. Melarsomine’s unconfirmed efficacy against stages less than 4 months old could present a problem in achieving the goal of eliminating all of the worms. The susceptibility gap between the macrocyclic lactones and melarsomine is demonstrated in Figure 6.
Figure 6. Timeline of D. immitis development, showing periods of susceptibility to macrocyclic lactones and melarsomine. The dotted line represents the “treatment gap,” when D. immitis is not considered to be susceptible to either treatment. From Merial Limited, Duluth, GA. ©2008. All rights reserved.
This gap can be eliminated by administering a macrocyclic lactone preventive for 2 to 3 months prior to administering melarsomine. This will eliminate the migrating larvae less than 2 months old and allow those worms between 2 and 4 months of age to reach an age at which they have been shown to be susceptible to melarsomine.
While controversial due to the theoretical risk of selecting heartworm populations that are resistant to macrocyclic lactones, it is beneficial to administer a macrocyclic lactone for up to 3 months prior to administration of melarsomine, when the clinical presentation does not demand immediate intervention. The logic for this approach is to kill susceptible heartworm larvae and thus prevent re-infection of the dog, while allowing less susceptible juvenile worms the opportunity to develop into more susceptible adult worms. The tactic increases the chance for removal of the existing heartworm infection when the adulticide injections are given later. Additional benefits of this protocol are the effects of macrocyclic lactones in greatly reducing, if not eliminating circulating microfilariae, stunting immature D. immitis and reducing female worm mass by compromising the reproductive system.
Exercise restriction should be rigidly enforced from the time of diagnosis through the period of treatment and recovery, with the most extreme degree of exercise restriction recommended for the first 4 weeks following melarsomine administration. Macrocyclic lactones administered as microfilaricides may cause a rapid decrease in the numbers of microfilariae and should be used with caution in dogs with high microfilarial counts. Pretreatment with antihistamines and glucocorticosteroids will minimize potential reactions.
Doxycycline
Many filarial nematodes, including D. immitis, harbor obligate, intracellular, gram-negative, endo-symbiotic bacteria belonging to the genus Wolbachia (Rickettsiales). Doxycycline reduces Wolbachia numbers in all stages of heartworms. Doxycycline administration during the first or second month following infection with heartworms was lethal to third- and fourth-stage heartworm larvae in experimental infections. In addition, in dogs with adult infections, doxycycline gradually suppressed microfilaremia.
Wolbachia have also been implicated as a component in the pathogenesis of filarial diseases, possibly through their metabolites. Recent studies have shown that a major surface protein of Wolbachia (WSP) induces a specific IgG response in hosts infected by D.immitis. It is also hypothesized that Wolbachia contribute to pulmonary and renal inflammation through its surface protein WSP. Studies have shown that similarly infected heartworm-positive dogs pretreated with ivermectin and doxycycline prior to receiving melarsomine injections had less pulmonary pathology associated with the death of the heartworms (Figure 7).
Figure 7. Top, Photographs courtesy of John McCall, PhD. Bottom, Photographs courtesy of Laura Kramer, DVM, PhD.
If incorporated into a heartworm treatment protocol, doxycycline should be given before administration of melarsomine so the Wolbachia organisms and their metabolites are reduced or absent when the worms die and fragment. Doxycycline is administered at 10 mg/kg twice daily (BID) for 4 weeks. Doxycycline has been shown to eliminate over 95% of the Wolbachia organisms in the filarial nematode Wuchereria bancrofti resulting in amicrofilaremia for 12 months. This data suggests that the absence or at least very low Wolbachia numbers are present as the organism is necessary for embryogenesis. Preliminary data indicate Wolbachia numbers remain low in D. immitis following doxycycline administration for at least 3 months.
ALTERNATIVE THERAPIES
Long-term Macrocyclic Lactone Administration
Slow-kill methods using continuous monthly administration of prophylactic doses of any macrocyclic lactone are NOT RECOMMENDED. While effective in reducing the life span of juvenile and adult heartworms, it appears that the older the worms are when first exposed to macrocyclic lactones, the longer it takes for them to die. The adulticidal effect of macrocyclic lactones may take more than two years of continuous administration before adult heartworms are eliminated completely, and rigid exercise restriction would still be required for the entire treatment period. Throughout this period, the infection would persist and pathology would continue to worsen. Another potential concern in using macrocyclic lactones long-term in heartworm positive dogs as stand-alone therapy is the potential for selection of resistant sub-populations of heartworms.
Macrocyclic Lactone/Doxycycline
In cases where arsenical therapy is not possible or is contraindicated, the use of a monthly heartworm preventive along with doxycycline might be considered. Studies have shown that administration of doxycycline in combination with ivermectin provided more rapid adulticidal activity than ivermectin alone. Anecdotal reports on other macrocyclic lactones with adulticidal properties suggest similar results but no confirmatory studies have been published.
Microfilariae from dogs treated with doxycycline that were ingested by mosquitoes developed into third-stage larvae that appeared to be normal in appearance and motility, but these larvae were not able to develop into adult worms, thus reducing the risk of selecting for resistant sub-populations. The administration of doxycycline at 10 mg/kg BID for a 4-week period every 3 to 4 months should eliminate most Wolbachia organisms and not allow them to repopulate. Exercise should be rigidly restricted for the duration of the treatment process. An antigen test should be performed every 6 months and the combination treatment continued until two consecutive negative heartworm antigen tests have been obtained.
Herbal Therapies
No “natural” or herbal therapies have been shown to be safe and effective prevention or treatment for heartworm disease.
Pulmonary Thromboembolism
Pulmonary thromboembolism is an inevitable consequence of successful adulticide therapy and may be severe if infection is heavy and pulmonary arterial disease is extensive. If signs of embolism (low grade fever, cough, hemoptysis, exacerbation of right heart failure) develop, they are usually evident within 7 to 10 days, but occasionally as late as 4 weeks after completion of adulticide administration. Mild embolism in relatively healthy areas of lung may be clinically inapparent. A pivotal factor in reducing the risk of thromboembolic complications is STRICT exercise restriction.
Steroids
Administration of diminishing anti-inflammatory doses of glucocorticosteroids helps control clinical signs of pulmonary thromboembolism. Whereas studies showed a decrease in efficacy of the arsenical thiacetarsamide when glucocorticosteroids were administered, a study showed no decrease in the efficacy of melarsomine when used in conjunction with prednisone. In highly endemic areas where animals are more likely to have significant worm burdens, glucocorticosteroids such as prednisone may be used. Prednisone is routinely dosed at 0.5 mg/kg BID for the first week and 0.5 mg/kg once daily (SID) for the second week, followed by 0.5 mg/kg every other day (EOD) for 1 to 2 weeks.
NSAIDs/Aspirin
The empirical use of aspirin for its antithrombotic effect or to reduce pulmonary arteritis is not recommended for heartworm-infected dogs. Convincing evidence of clinical benefit is lacking and there is some research suggesting that aspirin may be contraindicated.
AHS-Recommended Treatment Protocol
The AHS recommends a multi-modal approach to treating heartworms based on the information presented above and depicted in the following example management protocol (Table 3).
Table 3. AHS Recommended Management Protocol
Table 3. AHS Recommended Management Protocol
Day |
Treatment |
Day 0
|
Dog diagnosed and verified as heartworm positive.
Begin exercise restriction.
If the dog is symptomatic:
|
Day 1 |
Administer heartworm preventive.
|
|
Day 1-28 |
Doxycycline 10 mg/kg BID for 4 weeks
|
Day 30 |
Administer heartworm preventive. |
Day 60 |
Administer heartworm preventive.
Decrease activity level even further.
|
Day 90 |
Administer heartworm preventive. |
Day 91 |
3rd melarsomine injection2.5 mg/kg IM
Continue exercise restriction for 6 to 8 weeks following last melarsomine injections. |
Day 120 |
Test for presence of microfilariae.
Establish year-round heartworm prevention. |
Day 271 |
Antigen test 6 months after completion. |
SURGICAL EXTRACTION OF ADULT HEARTWORMS
Caval Syndrome (Dirofilarial Hemoglobinuria)
Caval syndrome develops acutely in some heavily infected dogs when adult heartworms partially obstruct blood flow through the tricuspid valve and also interfere with valve closure. Severe passive congestion of the liver, a coarse systolic murmur of tricuspid regurgitation, and jugular pulsations are characteristic features of the syndrome. The diagnosis is based on a sudden onset of severe lethargy, dyspnea, pale mucous membranes, and weakness accompanied by hemoglobinemia and hemoglobinuria. Caval syndrome can be confirmed conclusively by echocardiographic visualization of heartworms within the tricuspid orifice and posterior vena cava (Figure 8). The clinical course usually ends fatally within 2 days if surgical extraction of the worms is not pursued promptly.
Figure 8. Left, Echocardiogram image courtesy of Stephen Jones, DVM. Right, Echocardiogram image courtesy of Matt Miller, DVM.
Surgical removal of worms from the right atrium and orifice of the tricuspid valve can be accomplished using light sedation (may not be necessary), local anesthesia, and either a rigid or flexible alligator forceps or an intravascular retrieval snare introduced preferentially via the right external jugular vein. With fluoroscopic guidance if available, the instrument should continue to be passed until worms can no longer be retrieved (Figure 9). Immediately following a successful operation, the murmur should soften or disappear and within 12 to 24 hours hemoglobinuria should disappear. Fluid therapy may be necessary in critically ill, hypovolemic dogs to restore hemodynamic and renal function. Within a few weeks following recovery from surgery, adulticide chemotherapy is recommended to eliminate any remaining worms, particularly if many are still visible echocardiographically.
Figure 9. Photographs courtesy of Tom Nelson, DVM.
Pulmonary Arterial Infections
The main pulmonary artery and lobar branches can be accessed with flexible alligator forceps aided by fluoroscopic guidance. Intraoperative mortality with this technique is very low. Overall survival and rate of recovery of dogs at high risk of pulmonary thromboembolism is improved significantly by physically removing as many worms as possible before beginning adulticide therapy. When the facilities are available, worm extraction is the procedure of choice for the most heavily infected and high-risk dogs. Before electing this method of treatment, however, echocardiographic visualization of the right heart and pulmonary arteries should be performed to determine that a sufficient number of worms are in accessible locations.
CONFIRMATION OF ADULTICIDE EFFICACY
Clinical improvement is possible without completely eliminating the adult heartworms. Worms that do survive adulticide treatment are invariably the antigen-producing females. Most microfilaremic dogs with post-adulticide, female unisex infections become occult within 6 to 9 months, with or without microfilaricide treatment, and particularly if they are on a macrocyclic lactone preventative during and after adulticidal therapy. Consequently, clinical improvement and successful clearance of microfilariae from the blood do not verify a complete adulticide effect. Recurrence of microfilaremia 6 months later may be due to incomplete clearance of adult worms, maturation of immature worms if a preventive was not given during adulticide therapy or a new infection due to a lapse in chemoprophylaxis.
Heartworm antigen testing is the most reliable method of confirming the efficacy of adulticidal therapy. If all of the adult female worms have been killed, heartworm antigen should become undetectable by 6 months post treatment. However, this single test result does not verify that the dog is negative for heartworms, as larval and/or juvenile heartworms may be present in the dog and an insufficient amount of antigen is being produced by these young worms to elicit a positive test result. This is especially critical if a macrocyclic lactone was not administered prior to or initiated concurrently with adulticidal therapy. If a heartworm-positive dog is immediately treated with adulticide and a macrocyclic lactone is not given until 3 to 4 weeks after the last dose of adulticide, the dog should have a negative antigen test 7 months after the initial dose of macrocyclic lactone before being considered cleared of adult worms. Since adult worms may continue to die for more than a month following adulticide administration, dogs that are still antigenemic at any time less than 6 months post treatment should be allowed more time to clear antigen before retreatment is considered.
ELIMINATION OF MICROFILARIAE
No drugs are approved currently as microfilaricides by the FDA. Under the Animal Medicinal Drug Use Clarification Act of 1994, however, licensed veterinarians are permitted extra-label use of certain drugs having an established clinical application, if a valid veterinarian–client–patient relationship exists. The dispensing veterinarian is personally responsible for ensuring administration of the proper dose and providing appropriate aftercare when products are used in an extra-label application. The use of monthly administered heartworm chemoprophylactics as microfilaricides is governed by this regulation. Macrocyclic lactones administered as microfilaricides may cause a rapid decrease in the numbers of microfilariae and should be used with caution in dogs with high microfilarial counts. Pretreatment with antihistamines and glucocorticosteroids will minimize potential reactions.
Historically, microfilaricidal treatment was usually done about three weeks to a month after adulticidal therapy, with the understanding that several weekly treatments were often required to completely eliminate circulating microfilariae. Current protocols utilizing doxycycline in combination with regular preventive doses of macrocyclic lactones have essentially eliminated the need for post adulticidal elimination of microfilariae. Administration of a macrocyclic lactone should always begin as soon as the dog is diagnosed with a heartworm infection. Including doxycycline in the treatment protocol as previously described hastens the elimination of microfilariae.
When elimination of microfilariae is accomplished in the course of heartworm chemoprophylaxis, a microfilaria test should be performed in adulticide-treated dogs at the time the antigen test is conducted 6 months post treatment. Controlling the spread of heartworms entails decreasing the microfilaremic reservoirs of infection in the dog population and the benefits of doing so have been cited (see HEARTWORM CHEMOPROPHYLAXIS).
These guidelines are based on the latest information on heartworm disease. In keeping with the objective of the Society to encourage adoption of standardized procedures for the diagnosis, treatment, and prevention of heartworm disease, they will continue to be updated as new knowledge becomes available.
These guidelines are based on the latest information on heartworm disease. In keeping with the objective of the Society to encourage adoption of standardized procedures for the diagnosis, treatment, and prevention of heartworm disease, they will continue to be updated as new knowledge becomes available.
