Heartworm disease - Overview, intervention, and industry perspective

Abstract

Dirofilaria immitis, also known as heartworm, is a major parasitic threat for dogs and cats around the world. Because of its impact on the health and welfare of companion animals, heartworm disease is of huge veterinary and economic importance especially in North America, Europe, Asia and Australia. Within the animal health market many different heartworm preventive products are available, all of which contain active components of the same drug class, the macrocyclic lactones. In addition to compliance issues, such as under-dosing or irregular treatment intervals, the occurrence of drug-resistant heartworms within the populations in the Mississippi River areas adds to the failure of preventive treatments. The objective of this review is to provide an overview of the disease, summarize the current disease control measures and highlight potential new avenues and best practices for treatment and prevention.

Keywords: Animal health; Anthelmintic resistance; Dirofilaria immitis; Heartworm disease; Macrocyclic lactones; Mechanism of action.

Graphical abstract

Fig. 1

Adult D. immitis parasite. Photograph of a mass of adult D. immitis worms removed from a dog at necropsy. Most are female worms, but the coiled posterior end of a male worm can be seen in the middle of the mass.

Fig. 2

Dirofilaria immitis life cycle and chemical intervention periods. The inner circle represents the life cycle of D. immitis within the mammalian host (dog) and the vector (mosquito). The length of the arrows approximately reflects the development time of each stage. During a blood meal on an infected dog, microfilariae (mf) circulating in the blood are ingested by a mosquito. In the vector they develop into the larval (L) stages from L1 to infective L3, which can be transmitted during another blood meal to a mammalian host. Within the host they develop rapidly into L4 and finally to adult female or male parasites, which reside and mate in the heart (vascular and cardio pulmonary system, right heart chamber). The outer circle shows prevention and treatment options depending on the stage of development of the parasite. MLs are used as preventive treatment up to 60 days (d) post infection (0 d) against D. immitis L3 and L4 larval stages. After that period, efficacy of the MLs is no longer 100% (Bowman and Drake, 2017). Melarsomine, the only registered heartworm adulticide, is efficacious against adult D. immitis which can be diagnosed around 180 days post infection. Melarsomine administered in 2 doses 24 h apart also has substantial efficacy against juveniles, as shown in controlled studies (2017). However, melarsomine is not recommended to be used as a preventive or prior to definitive diagnosis of heartworm infection, but only for treatment of adult heartworms (https://capcvet.org/guidelines/heartworm/accessed November 27th, 2020). Ectoparasiticides or repellents can be used to prevent mosquitos from feeding on dogs and cats, reducing the potential for infection.

Fig. 3

Necropsy view of dog euthanized due to caval syndrome. D. immitis are indicated by arrows and clearly visible in the incised anterior vena cava (+). The lung lobe (*) is reflected back to the upper left, the trachea (x) is visible above the vena cava, and the pericardium and heart (#) are in the lower left of the image.

Fig. 4

Presence of D. immitis and D. repens infections throughout the world. Analyzing the number of dogs at risk for Dirofilaria infection, in Asia approx. 148 million dogs are at risk, in Latin America and Europe approx. 98 million dogs each, in North America approx. 80 million, in Africa approx. 50 million, and in Oceania approx. 6 million (López et al., 2012, Simón et al., 2012, Ramos-Lopez et al., 2016, Genchi and Kramer, 2019; Boehringer Ingelheim internal analysis).

Fig. 5

2019 heartworm incidence survey, American heartworm society. Heartworm incidence as shown in this map is based on the average number of cases per reporting clinic in 2019. Some remote regions of the United States lack veterinary clinics; therefore, no cases were reported from these areas. Used with permission from the American Heartworm Society https://www.heartwormsociety.org/.

Fig. 6

Structure of MLs marketed against heartworm infections. The macrocyclic core ring structure (top) indicates the regions where the MLs differ from each other. C13 is marked and highlighted in bold, where the main difference between the two major classes of MLs resides. Residues specific for each individual ML are visualized in blue. Modified following Prichard and Geary (2019).

Fig. 7

Structures of Non-ML heartworm APIs.

Fig. 8

Illustration of the binding site and opening of LGCC in response to IVM. (A) Five GluCl subunits, each consisting of four alpha helical structures (M1-M4) and an extracellular domain not shown here, adopt a pentameric tertiary structure. The transmembrane region is arranged with each subunit perpendicular to the plane of the membrane and the M2 helices (orange cylinders) of each subunit lining the interior channel. Chloride ions (green circles) flow down the concentration gradient (indicated by the green arrow) when IVM (yellow/orange wedge) binds at the interface of two GluCl subunits, inducing a shift in the helices and tilting of the M2 helices away from the center of the channel, effectively widening the extracellular portion of the channel. (B) An illustration of the electrophysiological response of GluCl to IVM. The closed state is represented by a static electrical potential (flat line) and circle with narrow pore, precluding chloride ion flow. Addition of IVM (yellow/orange arrow) induces an irreversible open channel conformation, illustrated by the right part of the trace and the circle with a large pore.

Fig. 9

Illustration of the putative components of D. immitis host pathogen interactions. A testable model for the ML in vivo mode of action can be constructed from the hypothetical interaction of ML, D. immitis, ES (variously colored circles), and the canine immune system (illustrated as various peripheral circulating morphonuclear cells). Microfilariae, and potentially L3 and L4 stages, broadcast a milieu of bioactive molecules that may specifically interact with host immune cells, abrogating a successful immune response that would clear the parasite. In the presence of MLs GluCls are engaged, neuronal signaling is silenced and the function of the ES apparatus (marked brown) shuts down. The resulting loss of ability to manipulate host immune signaling pathways results in clearance by a functional immune response.

Fig. 10

Local alignment of mdr1 wt and mutant mdr1 del4. Mdr1 wt from Canis lupus familiaris (Genebank accession number DQ068953.1) and mdr1 nt230 (del4) (Genebank accession number AJ419568.1) coding sequences as well as their transcripts were aligned. The nt230(del4) mdr1 deletion leads to a frame shift at amino acid position 75, resulting in a truncated, non-functional MDR1 protein due to the premature stop codon (TAA marked in red) after amino acid position 91.

Fig. 11

Consequence of mdr1 mutation for drug exposure in the central nervous system. (A) functional MDR1 receptor actively lowers concentration of APIs within the central nervous system, while (B) mdr1 mutation nt230 (del4), leading to a non-functional, truncated MDR1 channel, results in accumulation of APIs within brain cells, thus increasing susceptibility to neurotoxic side effects.

Fig. 12

Market shares of products based on specific APIs differ across geographies. As not all approved products are marketed anymore or in all geographies or might be marketed via channels not captured for this analysis, the API market analysis might be slightly skewed. One example are products containing besides MLs diethylcarbamazine citrate, a rather old API which has been replaced in more modern products. Data based on Boehringer Ingelheim internal market analysis, AH market 2019.