Heartworms

Advocate^®: Effective Against Heartworms

In general, non-intestinal filarial nematodes are characterized by their location in the deeper tissue of the host’s body and their dependence upon blood-feeding arthropod vectors for transmission. In companion animals, the most important filarial nematode with zoonotic potential is Dirofilaria immitis, the causative agent of canine cardiovascular dirofilariasis, better known as canine heartworm disease.

Canine Heartworm

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Canine Heartworm

Pathogenesis and Clinical Appearance

Heartworm disease is regarded as a serious and potentially life threatening disease in dogs and cats caused by the adult stages of Dirofilaria immitis.

The initial pathological findings are lesions of the endothelial cells of the pulmonary arteries. Swelling of the endothelium and adhesion of neutrophils and platelets causes lesions and allows albumin, plasma and blood cells to escape perivascularly. These endothelial changes are followed by intimal swelling and further changes in the internal arterial surface. Proliferation of the endothelium is reported to be directly related to the duration of infection as well as the worm burden. Following the vascular changes, the leaking of proteins and fluid into the lung tissue causes edema of the lung parenchyma. These changes may be seen 3 to 5 months post infection.

Due to the reduced function of the pulmonary arteries, a „Cor pulmonare“ with hypertrophy and dilatation of the right ventricle occurs, indicating right-sided congestive heart failure. Spontaneous death of worms can produce thromboembolism and severe inflammation.

The development of clinical signs in dogs occurs with a high level of individual variation and is dependent upon duration of the infection, the worm burden, and the activity of the dog. In general, exercise leads to more severe clinical signs of disease. Coughing is the first sign of infection, together with exercise intolerance and abnormal lung sounds. With the presence of congestive heart failure, ascites, dyspnea, tricuspid cardiac murmur and hemoglobinuria are typical clinical signs.

Diagnosis

For diagnosis of Dirofilaria immitis infection, parasitological, immunological and molecular techniques are available.

The parasitological test methods are filter-tests, the hematocrit-method, the Modified Knott’s test or a direct blood test. All of these tests are useful in identifying a patent infection by the detection of circulating microfilaria. For the ‘Modified Knott’s test’, 1 ml of EDTA blood mixed with 9 ml of a 2 % formalin solution is centrifuged. The sediment will contain the microfilaria. Through using methylene-blue dye, lysis of the erythrocytes occurs and the stained microfilaria are better visible. For fast detection in the clinic, one may use fresh drops of EDTA-blood mixed with physiological saline solution on a slide for direct microscopic examination. For the ‘filter test’, the microfilaria will be examined after blood has been pressed through a fine filter-membrane. With the hematocrit method, microfilaria will be present just above the buffy coat of leukocytes. All of these methods are highly specific, while the sensitivity may vary. Microfilaria are not present in dogs with pre-patent infections or in those with occult infections.

Immunological methods are frequently used today in detecting circulating antibodies or antigens. Tests detecting antibodies produced against an infection with Dirofilaria were the first commercially available test kits. Today, antigen tests are in place both for in-clinic use, as well as through diagnostic laboratories. Test sensitivity today will allow for detection of an infection with one or more adult female worms. Sensitivity decreases in infections with pre-patent worms of less than 5 months of age.

Clinical Efficacy of Advocate^®

During the process of product development, dose determination and dose confirmation studies with a range of endo- and ectoparasites in both dogs and cats were carried out.

In these studies, the dose rate and concentration of imidacloprid was fixed to 10 mg/ kg body weight and so was the dose volume. For moxidectin, it was necessary to adjust the dosage by adding different concentrations of moxidectin to the formulation. In general, moxidectin is reported to be highly effective against heartworm larvae even at very low dosages. In these dose finding studies, followed by dose determination studies, it was concluded that pre-adult D. immitis were not the dose limiting parasites. Rather, gastrointestinal nematodes required a higher dosage than that necessary for heartworm control.

All following heartworm studies were conducted using the 2.5% moxidectin concentration.

A study was conducted to determine the efficacy of Advocate on 45 day old heartworm larvae.¹ In this study, dogs were experimentally infected with 50 L3 larvae removed from Aedes aegypti mosquitoes. At day 45 post-infection, dogs were either treated with Advocate or one of the two actives, imidacloprid or moxidectin alone.

All dogs were examined for the presence of adult heartworms at day 164 post-infection (day 119 post-treatment). No adult heartworms were recovered from the Advocate-treated dogs, nor the moxidectin-treated dogs. However, a mean number of 37.6 adult D.immitis were found in the imidacloprid-only treated dogs.

Feline Heartworm

Pathogenesis and Clinical Appearance

Cats are a suitable host for D. immitis, however they are somewhat less susceptible to heartworm infections. If cats get infected with heartworms, they typically harbour low umbers of worms, usually less than 6 adult worms, often of the same sex. Higher worm burdens have been reported, however, this is a rare finding. Worms that make it to maturity are smaller in size than those of patently infected dogs and the life span appears to be only 2 to 3 years, in comparison to 7 years and more in dogs. The pre-patent period is reported to be 8 months and, thus, 2 months longer than in dogs. Adult worms may be present, however microfilaremia is unusual. In general, it appears that cats are capable of eliminating worm infections spontaneously. All of these factors contribute to the fact that the prevalence of heartworm infections in cats in endemic areas is underestimated. The reasons for this include unclear or transient clinical signs, limitations in diagnostics, or, in some cases, sudden death without confirmation of the presence of heartworms.

In contrast to dogs, small numbers of heartworms are potentially life-threatening to cats. The affected organ is the lung and the pulmonary arteries. Clinical signs develop when the immature adults enter the pulmonary arteries, which may result in acute inflammation of the vessels or the lung parenchyma. Macrophage numbers increase dramatically. This first phase of infection is reported to coincide with either severe clinical signs or even death. In cats that overcome this stage, heartworms develop to the adult stage. The following phase of patent infection may be either without clinical signs or that of a chronic unspecific infection with coughing, asthma-like signs, dyspnea, lethargy and the like. A second life-threatening stage is the spontaneous dying and degeneration of adult worms. This may cause inflammation of the lungs and thromboembolism.

Diagnosis

Diagnosis of heartworm infection in cats is more complicated than that in dogs. Circulating microfilaria are absent, clinical signs are often unspecific and radiography might miss the typically low worm burden. Additionally, diagnostic test kits developed for detection of canine heartworm infection are based on circulating female antigens, and these antigens may be absent in cats.

Today, specific antibody test kits are available for diagnosis in felines. In general, it may be advisable to implement several different diagnostic tools to either determine heartworm infection in a cat or exclude heartworm infection in a cat with unspecific clinical signs.

Clinical Efficacy of Advocate^® - Heartworm Prevention in Cats

For evaluation of heartworm prevention, Advocate was studied in experimentally infected cats. In a critical efficacy study, Advocate was tested in comparison to imidacloprid, moxidectin and a placebo treated control group².

Ten cats per group were infected with 100 L3 D. immitis on study Day -30 and treated on Day 0. In a follow up efficacy confirmation study, 20 cats were infected with 100 L3 larvae each 30 days prior to treatment. Cats were treated using Advocate on day 0 at moxidectin dosages between 1.04 to 1.69 mg/ kg b. w. Heartworm antigen tests were performed using the DiroCHEK test prior to infection on Day –35 and at day 90 post infection. All cats tested antigen negative on both days. On final examination day 140 pt. (170 dpi), all cats in the Advocate treated group were heartworm negative, while 31 adult heartworms were recovered from 8 of the 10 infected cats (average 3.25 adult HW/ cat).