Dirofilariasis in Dogs and Cats

Infection with Dirofilaria immitis has a world-wide distribution and has been reported to infect a wide variety of species of animals (dog, cat, ferret, fox, wolf, sea lion, horse). The distribution is influenced by a resevior population of animals (dogs usually) that complete the life-cycle and have microfilaremia, and a mosquito vector that will complete the early larval stages. Different mosquito feeding patterns influence the areas and species of animal infected. For a cat to develop heartworm disease, the mosquito must fed on a dog and then after adequate warm environmental exposure, fed on a cat.

Adult females (27 cm long) and males (17 cm long) normally reside in the pulmonary arteries and right ventricles without causing major occlusion of blood supply. Microfilariae (315 um long and 6-7 um wide) are discharged into the blood stream and survive 1-3 years. The number of circulating microfilaria in dogs is increased in warm ambient temperature, after eating, and late at night. The microfilariae are ingested by a mosquito during feeding. The infective larvae (L1) migrate to the stomach and then the mouthparts (L3) during development. The rate of development can be as short as 8 days at 30^oC or as long as 28 days at 18^oC. After a mosquito acquires the microfilaria (L1), adequate exposure to warm temperatures must occur during the relatively short life span (1 month) of that mosquito. The infective larvae are deposited on the skin of an animal when the mosquito feed again and the L3 enters through the bite wound. A maximum of 10-12 L3 can be transmitted by a single mosquitos.

The L3 stages molt and migrate to the pulmonary arteries arriving as L5 (1-2 cm long) approximately 100 days after infection. These small L5 are distributed mainly to the caudal distal pulmonary arteries and over the next 2-3 months, develop to sexually mature adults and migrate back toward the right ventricle. If both sexes are present, microfilaria are produced 6-7 months after L3 exposure. The detection of circulating adult antigen can occur before or after the production of the initial microfilaremia. The initial arrival of L5 in the small vessels of the lungs is associated with an intense eosinophilic reaction and a diffuse radiographic pattern and clinical signs of coughing may be present; preceding the production of microfilaria and circulating antigen by 2-3 months. Clinical diagnosis of early disease is difficult at this stage especially in the cat and ferret. No pathology has been associated with circulating live microfilaria.

Adult heartworms can live 3-5 years. Although a endarteritis is produced, embolization and vascular occlusion is rare when the worms are alive. The severity of the pathology is influenced by the number of parasites but also exacerbated by the shear stress of high blood flow associated with exercise. Severe pathology can be induced by low worm burdens in athletic dogs. The classically described cor pulmonale syndrome is only induced in dogs with an exercise pattern forcing right ventricular hypertrophy from increased cardiac outputs and increased pulmonary vascular resistance. In endemic areas, the average worm burden in the dog is about 15 worms and in the cat 1-3 worms. High worm burdens can be found in dogs with minimal cardiac changes if the dog is senitary. The death of worms, either spontaneous or induced, is associated with severe pulmonary parenchymal disease. Respiratory failure may result and in the cat and ferret can be associated with a single worm infection.

High worm burdens (>75) can be demonstrated in acute post-caval syndromes and chronic ascites from tricuspid valve dysfunction. Because of the increased resistance of most animals from repeated exposure to L3 over time, high worm burdens are most likely to occur in dogs which have not been exposed to any mosquitoes with L3 previously and are then bitten by many mosquitos over a 3 month time period.

Clinical Finding:

The clinical signs of heartworms is dependent on the stage of the life cycle, severity of infection, and host response to the infection. Early clinical signs of L5 may be coughing associated with the eosinophil pulmonary response. An active dog may develop exercise intolerance because of decreased cardiac output. Non-specific signs of weight loss, fever, and dyspnea can occur in severe disease. Ascites may develop in right sided heart failure from cor pulmonale or mechanical dysfunction of the tricuspid valve as in postcaval syndromes. Many dogs and cats are asymptomatic during stages of the infection, but subclinical disease may decrease the quality of life of the pet. In approximately 10% of dogs with heartworms, microfilaria are produced but an intense host immune reaction clears the microfilaria and severe pulmonary reactions are observed with coughing being the primary clinical sign.

Clinical signs in cats have been primarily intermittent respiratory disease (coughing and/or dyspnea) or sporadic vomiting unassociated with eating. The respiratory signs mimic those of bronchial asthma and are initially corticosteroid responsive. Initial respiratory signs often occur 4-6 months after the peak mosquito season. Non-specific signs of weight loss and anorexia without respiratory or GI signs do occur in some cats. Right sided heart failure is rare in cats and is usually associated with a high worm burden (> 7 worms).

Cats may present with acute dyspnea and or collapse with no previous respiratory signs. Acute death associated with this presentation is common and often confused with bronchial asthma. Complete necropsy with emphasis on distal pulmonary arteries may be required to demonstrate the parasite in cats.

Diagnosis:

Demonstration of the microfilaria of D immitis in a blood sample is successful with concentration techniques (modified Knotts' and filter tests) in about 60% of dogs and <10% of cats with heartworms. Because of the survival of microfilaria after adults have died, a small percentage of dogs can have microfilaremia but no adult in the heart. In addition, puppies born to bitches with high microfilaria count can have a transient microfilaremia, which cannot become an adult infection. Amicrofilaremic animals (occult infection) can be caused by immature (<6 month old) worms, single worm infections, unisex infections, host immunologic reactions to microfilaria, and iatrogenic production of occult disease. The monthly preventative medications will induce embryo stasis in the female heartworm and after 6 months of medication in a heartworm positive dog, an occult status has been demonstrated in most dogs. Antigen testing is necessary to determine the heartworm status of a dog on monthly preventatives.

The detection of circulating antigen is based on a laboratory derived antibody binding to an adequate amount of circulating heartworm antigen. Although the glycoprotein detected by most assays is found throughout the parasite, the major source of circulating antigen is the mature female reproductive tract. The maturity and number of females influences the amount of antigen. Immature worms and low worm burdens (especially in the cat) will be antigen negative even when worms are present in the pulmonary arteries and clinical signs are present.

Thoracic radiographs can be a screening tool for dogs and cats with suggestive clinical signs of heartworm disease. The pulmonary arteries can be tortuous and enlarged in dogs with an enlarged pulmonary arterial segment at the 1 o'clock position on a VD view. Right ventricular enlargement may not be noted if the hypertrophy has not been induced by physical activity or severe vascular lesions. The pulmonary parenchymal changes can be diffuse in the early L5 infection, but can also become granulomatous in chronic severe infections. In the cat, cardiac changes are rare and even an enlarged pulmonary arterial segment on the VD view is not visible beyond the cardiac shadow. Enlarged caudal pulmonary arteries are the most consistent lesion in cats with heartworms. Severe lung parenchymal changes may obscure the vascular pattern. A fluid density lung lobe is associated with acute signs in cats and may be confused with a consolidating pneumonia.

Echocardiograms are diagnostic with the typical "double parallel" white lines are noted in the pulmonary arteries or right ventricles of dogs or cats. Echocardiograms are especially useful in diagnosis of post-caval syndromes and ascitic condition associated with heartworm disease. The electrocardiogram will only have the typical right axis deviation and deep S waves if there is significant right ventricular hypertrophy.

Tracheal cytology is usually non-specific and is rarely positive for bacteria in either the dog or cat. An eosinophilic cytology is usually a stage specific reaction.

Treatment of Dogs with Heartworms:

Attempts to decrease the clinical significance of the heartworm lesions have been unsuccessful with aspirin, aspirin and dipyridamole, serotonin antagonist, short-acting heparin, and high dose corticosteriods. Abnormal pressor vessel dynamics and pulmonary parenchymal damage may contribute to the failure of these agents. Because of the pressure overload of heartworm disease, digitoxin is usually not recommended. Angiotensin converting enzyme inhibitor may be used in severe right ventricle hypertrophy. The interstitial edema associated with acute symptoms of worm death is not aided by diuretic therapy.

Routine therapy included: 1. Pre-therapy diagnostic to determine sub-clinical disease, especially of the liver and kidney. 2. Adulticidal therapy to eliminate mature worms. 3. A rest period of 4-6 weeks to allow the animal to recover from the lung injury associated with worm death. 4. Micro filaricidal therapy if required. 5. Post-Micro filaricidal check. 6 Antigen test to determine success of adulticidal therapy. 6. Preventative medications.

Adulticidal therapy eliminated the adult parasite and allow the host to repair the damage where fibrosis has not occurred. Death of the worms in both dogs and cats is associated with severe parenchymal lung damage and limited exercise is essential during the post-adulticidal phase. Platelet consumption and coagulopathies develop in most dogs 2-3 weeks after adulticide. Thiacetarsamide (4 IV doses over 2 days) will kill most males and some females but has poor efficacy against immature worms and young females. Arsenical toxicity cannot be predicted in clinically normal dogs based on laboratory tests. Melarasmine (2 IM doses over 24 hours) has improved efficacy (>95% kill). Increased worm death can cause serious complication in dogs with high worm burdens and one IM dose and a 1 month recovery period followed by the 2 IM doses is a safer alternative in dogs with severe heartworm disease or high antigen loads, suggesting large worm burdens. No agents as a pre-treatment have been successful in decreasing the complication rate. Dogs should be rested for 4-6 weeks.

Complications of worm death often include impaired pulmonary function and vessel damage may initiate DIC. Dyspnea after adulticide in a dog should be considered an emergency. Nasal oxygen and immediate acting glucocorticoid at shock doses are needed to provide adequate oxygenation and decrease the acute lung injury. A platelet count below 100,000/ul is not uncommon, but a activated clotting time should be performed to determine if DIC is present. DIC carries a poor prognosis in heartworm dogs. Many dogs will respond within 24 hours after the crisis. Because of the fragile nature of the capillary beds of the lungs, no exercise or stress should be allowed during this time.

Microfilariacidal therapy includes no FDA approved drug at this time. Thus, ivermectin at 50 ug/kg or milbemycin at the preventative dose will be effective within 2-3 weeks. Most microfilaria are killed quickly and reactions are associate with small dogs with high microfilaria counts and usually occurs within 1 hour of administration. Concentration techniques should be used to assess microfilarial status.

Antigen assays 12-16 weeks after successful adulticidal therapy should be negative. Low worm burdens and immature worms can still be present with a negative antigen test. Positive antigen tests should be rechecked in 1 month before initiating a second adulticidal regimen.

Preventative:

Diethylcarbamazine, ivermectin, and milbemycin oxime are orally administered preventatives. Before preventative medications are administered, dogs over 6 months of age should be negative for microfilaria and antigen assay. Dogs under 6 months should be rechecked 6 months - 1 year after initiation of therapy for microfilaria and antigen. Dec should be administered daily for 1 month before the mosquito season until 2 months after the season. Ivermectin and milbemycin oxime should be administered once monthly for 1 month after the onset of the mosquito season until 1 month after the endo of the season. Temperate areas and use of the preventatives for other parasite control may use the monthly product year round. Dogs on monthly preventative should have antigen assays to determine the heartworm status. Preventative products should not be administered to microfilaria-positive dogs.

Therapy in cats with heartworms: After the diagnosis of feline heartworm disease has been confirmed, the therapeutic considerations must be carefully discussed with the client. The nature of feline heartworm disease to cause chronic vomiting, intermittent respiratory signs, or to be asymptomatic often misleads the client into thinking the disease is less severe than it is. Spontaneous acute complications and death in a small percentage of cats can occur. Therefore the client must be warned that withholding therapy can be lethal in a minority of cases. In the asymptomatic cat, this risk appears to be small compared to the complications of adulticidal therapy. Because the adult heartworm has a shortened longevity in the cat compared to the dog, the possibility of spontaneous recovery should also be discussed. In the cat with recurrent dyspnea that is life-threatening or with clinical signs that are unacceptable to the owner, adulticidal therapy has been used safely and should be considered.

Therapeutic Plan

Treatment of feline heartworm disease with thiacetarsamide sodium (2.2 mg/kg IV, bid, two days) is tolerated by cats without immediate complications of hepatotoxicity or renal toxicity. The use of ketamine as a sedative to aid in careful administration of thiacetarsamide is recommended in active cats. There are occasional reports of acute symptoms after thiacetarsamide injections, but slow injections have not caused acute collapse in normal healthy cats in this author's experience. Pulmonary edema as a complication during the two days of injections has been observed and oxygen therapy and corticosteroids should be considered if dyspnea and/or cyanosis occurs. This complication cannot be predicted.

In the symptomatic cat, clinical signs tend to improve after therapy. However, chronically anorexic cats may require hyperalimentation. Although the presence of circulating microfilaria is uncommon, dithiazanine iodide and levamisole hydrochloride have both been used successfully as microfilaricides.

Post Adulticidal Complications

Complications after therapy are usually related to embolization. The complication of pulmonary edema and cyanosis warrants further consideration but has not been consistent with this author's experience. Sudden death from embolization can occur especially within the first 10 days after adulticide administration. Embolization can induce severe lung infarction, hemoptysis and dyspnea. Severe thrombocytopenia has not been noted. Based on the assumption that heartworm mass is related to antigen load, a cat with a "strong positive" antigen test would be more likely to develop post-adulticide complications than a cat that has a low worm burden and is antigen negative or "weakly positive."

Embolization most often affects the caudal lung lobes and thoracic radiographs may demonstrate a lung lobe with increased density, Oxygen therapy is indicated if hypoxemia or dyspnea occurs. High doses of corticosteroids (1-2 mg/lb of prednisolone three times a day) with careful IV fluid therapy will often support the cat through the crisis. The routine use of corticosteroids is not recommended before or after thiacetarsamide in cats.

Based on current information, there is evidence that aspirin may inhibit prostaglandin formation and thus increase leukotriene production in the lung; the result would be bronchospasm and pulmonary hypertension. It is not currently recommended that aspirin be used in feline heartworm disease and it may be contraindicated when acute embolization occurs.

The peracute nature of the post-adulticide reaction dictates that the cat be under constant attention, especially during especially during the first two weeks. The clinical and radiographic signs of acute embolization can resolve over one to two days. However, death can be so rapid that is occurs before therapy can be instituted. The client should be aware that the risk of complications in the cat seem to more severe than in the dog. The severity of the post-adulticidal reaction poses a dilemma for the veterinarian and the risk of post-adulticide complications probably is a greater risk than that from the spontaneous death of heartworms in the asymptomatic cat and the resultant embolization.

Efficacy of Treatment

Although heartworms in cats may not live as long as in dogs, clinical signs and even death may occur. The efficacy of thiacetarsamide cannot be evaluated in many client cats because of the occult nature of the disease. However, of cats that have had microfilariae, repeated attempts to eliminate microfilariae have failed and repeated adulticidal therapy has been required in some. Problems associated with efficacy were alluded to in other microfilaremic cats. However, current research seems to indicate that the adulticide is effective and clinical signs usually abate during the initial weeks after thiacetarsamide. If a cat was antigen positive before therapy, the antigen test should be negative 12 weeks after adulticide therapy. A positive test at this time would indicate the presence of adult heartworms after the adulticide. Melarsomine has not been evaluated in cats for routine clinical use.

Patient Discharge Information

In cats with intermittent clinical signs or in the case where owners will not accept the potential risk of adulticidal therapy, the owner should be educated as to the nature of the peracute signs of embolization. An emergency dose of prednisolone (5 mg/kg per os) should be dispensed to be administered if collapse or dyspnea are noted. The onset of acute respiratory signs in a heartworm cat is a true emergency requiring immediate care. The radiographic signs of severe lung pathology should not be over-interpreted as "consolidation or pneumonia." The initiation of oxygen therapy, cage rest, small volumes of intravenous fluids, and injectable prednisolone has resulted in clinical improvement and resolution of radiographic signs within 24 hours of presentation in some cats with life-threatening dyspnea and collapse.

Preventive Medication

In highly endemic areas with vector populations (dogs) providing the mosquito with a reservoir, the incidence of heartworms in cats (20 percent) would indicate that preventives are indicated. In non-endemic areas the incidence is not sufficient to warrant preventive therapy in cats. Infection from D. immitis in cats can be prevented with 500 ug/kg of melbramycin or 25 ug/kg of ivermectin administered per os once a month. In endemic areas it is suggested that preventative medication be administered at 4-6 weeks of age and continued for the life-span of the cat. Although heartworm disease may be of low incidence in many areas, the high rate of complications associated with feline heartworm disease would make preventative medications an attractive alternative. Although heartworm disease can be self-limiting in many cats, the potential to initiate inflammatory lung disease and predispose to bronchial asthma may prove to be adequate indications for preventative medications.