Dirofilaria immitis (ie, canine heartworm) is the causative agent of heartworm disease in dogs and cats and has wide global distribution.1 In the United States, D immitis infection has been diagnosed in all 50 states, and cases of macrocyclic lactone resistance have been documented. FDA-approved preventives are available for dogs and cats, but pharmaceutical treatment is only available for dogs.
Life Cycle
The main reservoirs of D immitis are dogs and wild canids. Adult worms mate and produce microfilariae that circulate in the blood. A mosquito, the intermediate host, ingests the microfilariae, which then molt twice to become infectious third-stage larvae (L3) and migrate into the head of the mosquito over an average period of ≈10 to 14 days. When the mosquito lands on a host and consumes a blood meal, L3s are deposited on the host’s skin.1 The larvae enter the host through the bite wound and migrate primarily in the subcutaneous tissue and musculature, where they molt 2 more times. After 67 to 120 days, the worms arrive in their final location, the pulmonary artery, but are not yet detectable by antigen or microfilariae tests. Heartworm antigen may be detected by as early as 150 days postinfection.2,3 By day 180, worms are sexually mature and begin to produce microfilariae.3
Prevention
The cornerstone of heartworm disease prevention is regular, lifelong administration of a macrocyclic lactone, starting as early in life as possible (4-8 weeks of age, depending on the preventive). Administration of macrocyclic lactones at regular intervals kills migrating larvae in the tissue before they reach the pulmonary artery. Heartworm preventives are therefore prophylactic rather than anti-infective, as worms must infect the host before the drugs can be effective.1
Four molecules in the macrocyclic lactone class—ivermectin, milbemycin oxime, moxidectin, and selamectin—are available in FDA-approved preventives for dogs as single compounds (milbemycin oxime, moxidectin, selamectin) or in combination with other drugs (ivermectin, milbemycin oxime, moxidectin). These 4 molecules, as well as eprinomectin, are available in FDA-approved preventives for cats. Preventives for dogs are available in oral (ivermectin, milbemycin oxime, moxidectin), transdermal (selamectin, moxidectin), and injectable (moxidectin) formulations. Preventives for cats are available in oral (milbemycin oxime) and transdermal (selamectin, moxidectin, eprinomectin) formulations.1
The primary mechanism of action of macrocyclic lactones is hypothesized to be hyperpolarization of glutamate-gated chloride channels. These chloride channels may function in excretion and/or secretion of certain substances produced by the parasite that may protect the worm by altering the host immune system or preventing host recognition of tissue-dwelling larvae.4-6 Macrocyclic lactone administration is postulated to prevent excretion and/or secretion of these substances, thereby allowing the host immune system to recognize and eliminate the worm.
Treatment & Management
Medical Treatment in Dogs
Melarsomine is the only FDA-approved treatment for adultheartworm infections in dogs.1 The American Heartworm Society (AHS) recommends a treatment protocol that includes melarsomine, prednisone, doxycycline, a macrocyclic lactone, and a mosquito repellant or isoxazoline.
Mechanisms of Action
Melarsomine, an arsenical drug, is a metabolic poison that kills adult heartworms, likely through disruption of aerobic metabolism.7
Prednisone, a corticosteroid, reduces inflammation associated with heartworm death.1
Doxycycline, a bacteriostatic tetracycline antibiotic, helps eliminate Wolbachia spp, the filarial bacterial endosymbiont commensal with all stages of the heartworm life cycle.8 Wolbachia spp contribute to the inflammation and clinical signs associated with adulticidal therapy; eliminating these bacteria can reduce these effects.9-11
The proposed mechanism of macrocyclic lactones is described in Prevention. The main purpose of administering these drugs during heartworm treatment is to prevent subsequent heartworm infection.
EPA-labeled repellents can repel mosquitoes before they feed on dogs.12 Isoxazolines kill mosquitoes after the mosquito feeds and before microfilariae can progress to L3, preventing transmission of D immitis to other hosts.13-17
Treatment Protocol
The AHS recommends monthly administration of a macrocyclic lactone preventive starting at diagnosis, a 28-day course of doxycycline (10 mg/kg PO every 12 hours) starting at diagnosis, and a 3-dose protocol of melarsomine (2.5 mg/kg IM; 30 days between first and second injections, 1 day between second and third injections) starting 2 months after diagnosis.1 The doxycycline dose may be reduced to 7.5 or 5 mg/kg PO every 12 hours if the initial dose is not well tolerated (eg, patient displays signs of nausea).1,18 The 3-dose melarsomine protocol is recommended regardless of clinical signs, except in cases of caval syndrome, which require surgical treatment (see Surgical Treatment in Dogs).1 Exercise restriction is recommended throughout treatment.1
Administration of a tapering, anti-inflammatory dose of prednisone (0.5 mg/kg PO every 12 hours for 7 days, then 0.5 mg/kg PO every 24 hours for 7 days, then 0.5 mg/kg PO every 48 hours for 14 days) is recommended in conjunction with the first and third melarsomine injections. Patients with clinical signs should also be given prednisone in conjunction with doxycycline.1
A 1-month delay between treatment with doxycycline and melarsomine is likely necessary for further reduction of Wolbachia spp bacteria and degradation of proinflammatory Wolbachia spp proteins.19 During this time, worms are hypothesized to eliminate the bacteria killed by doxycycline. Neither pathology nor worm size increases during this period.18
Surgical Treatment in Dogs
Surgical removal of worms via jugular venotomy is typically only performed in cases of caval syndrome.1
Posttreatment Recommendations in Dogs
One month after the last dose of melarsomine is administered, dogs should be screened for microfilariae. If microfilariae are present, a microfilaricide should be given and screening repeated after 4 weeks. The only FDA-approved microfilaricide is 10% imidacloprid with 2.5% moxidectin administered at the label dose.
Antigen tests should be used to determine the efficacy of adulticidal treatment. If all worms are killed, adult antigen should be undetectable by 9 months after the last injection of melarsomine; however, if heartworm antigen remains detectable, retreatment with continued monthly administration of a heartworm preventive, a 28-day course of doxycycline, and 2 melarsomine injections administered 24 hours apart 30 days after completion of doxycycline is recommended.1 Administration of a tapering, anti-inflammatory dose of prednisone is recommended in conjunction with the first and second/third melarsomine injections.
Medical Treatment in Cats
No effective pharmaceutical treatments are available for heartworm disease in cats.