Dirofilaria immitis

Also known as: heartworm disease.

Do not confuse with: Angiostrongylus vasorum, angiostrongylosis.

Description

Dirofilaria immitus - Courtesy of the Laboratory of Parasitology, University of Pennsylvania School of Veterinary Medicine

Dirofilaria immitis is a nematode parasite that causes heartworm disease in dogs, cats and ferrets. Heartworm disease is transmitted by mosquito bites and there are more than 70 species of mosquito that are able to transmit infection; Aedes, Anopheles and Culex are the most common vector species. Heartwoem disease has been reported in many countries with temperate and is particularly prevalent in the USA, Canada, and southern Europe. The introduction of the PETS travel scheme has increased the concern over Dirofilariasis in the UK.

Dirofilarias does have zoonotic potential: infected mosquitos can transmit Dirofilaria immitis to humans, but the infection does not become patent. The infective larvae instead reach the lungs, become encapsulated, and die causing granulomatous reactions called "coin lesions" in the process. These are only imporant because they may be confused with neoplastic metastasis to the lungs on radiography¹.

Life Cycle

Dirofilaria immitis adults reach maturity and sexually reproduce in the pulmonary arteries and right ventricle. Adult males are around 15cm in length, and females are around 25cm¹. After mating, female worms release larvae known as microfilariae (or L1) into the circulation. When a mosquito takes a blood meal from the infected dog or cat, microfilariae are ingested. Mosquitos are true intermediate hosts for Dirofilaria immitis, since microfilariae require a period of maturation to L2 then L3 in the vector. The duration of this development depends upon environmental conditions. For example, maturation at 30°C takes around 8 days, but when temperatures are down to 18°C, this takes around one month². Below 14°C, development is halted and resumes when temperatures rise. In cooler climates, this means that transmission of heartworm disease to new canine or feline hosts can only occur in warmer months.

Once matured, L3 in the mosquito migrate to the labium, from which they erupt onto the host's skin as the mosquito feeds. Larvae then migrate into the bite wound and, as most dogs are highly susceptible to heartworm disease, most L3 then establish infection. It takes 2-3 days for L3 to moult to L4, which remain in the subcutaneous tissues for up to two months before becoming young adults (L5) and migrating to the pulmonary arteries.

Cats differ from dogs in that they are more resistant to infection with Dirofilaria immitis. A lower percentage of exposed cats develop adult infections, and when this does occur the burden is usually low¹. L5 in the pulmonary arteries also have a relatively short (2 year) survival time in cats.

Pathogenesis

Heartworm disease primarily affects the cardiopulmonary system and the severity and extent of lesions depends several factors. These include the number and location of adult worms^{1, 2}, the duration of infection, and the level of activity of the host¹. Parasites in the pulmonary arteries cause mechanical irritation, leading to endothelial damage, proliferation of the intima and perivascular cuffing with inflammatory cells. This results in narrowing and occlusion of the vessels which in turn causes pulmonary hypertension. A combination of pulmonary hypertension and inflammatory mediators can lead to in an increase in the permeability of pulmonary vessels, giving periarterial oedema and intersitial and alveolar infiltrates. Eventually, irreversible interstitial fibrosis arises.

Sequelae to heartworm infection include pulmonary thromboembolism, which can either occur due to the death and metastasis of adult worms, or due to platelet aggregation induced by the parasite. In severe cases, live nematodes can migrate to the right ventricle, right atrium and caudal vena cava. The resulting incompetence of the tricuspid valve, augmented by concurrent pulmonary hypertension, leads to signs of right-sided heart failure. Flow of erythrocytes through the mass of parasites formed can also cause haemolysis and thus haemoglobinaemia. This combination of acute right-sided heart failure and intravascular haemolysis is referred to as "caval syndrome", which in severe cases can also be characterised by thromboembolic events and disseminated intravascular coagulation. Due to the smaller numbers of adult worms, caval syndrome is less common in cats².

In cats, heartworm disease generally causes a diffuse pulmonary infiltrate and an eosinophilic pneumonia². Adult worms may die and embolise to the lungs, resulting in severe haemorrhage and oedema of the affected lobe. Immature nematodes have also been known to migrate to sites other than the pulmonary arteries and heart such as the CNS, eye and subcutaneous tissues. These ectopic infections are far more common in cats than in dogs, suggesting that D. immitis is not well adapted to feline hosts.

Signalment

Dirofilaria immitis infection affects dogs more commonly than cats, and risk is greatest in outdoor animals. Dogs of any age may be affected, but infections are most common in 3 to 8 year old dogs, and medium and large breeds are over-represented^{1, 3}. In cats, there are no breed or age predispositions, but males are more frequently affected³. Ferrets may also contract dirofilariasis; there are no age or sex predilections¹.

Diagnosis

Clinical Signs

In dogs, historical findings at the time of presentation can vary. Some animals are asymptomatic, or cough only occasionally. In countries where heartworm is endemic, animals may be routinely tested for dirofilariasis at the end of the high-risk season, when weather becomes cooler³. Therefore, positive laboratory testing may be the first indication of disease¹. More obvious signs may be seen depending on the severity of disease. Generally, the onset of heartworm disease is insidious, and clinical signs are related either to a high parasite burden, or to an allergic response to the parasite². Affected dogs most often show coughing, and dyspnoea/tachypnoea, exercise intolerance, loss of condition and syncope may also be seen. In severe cases the pulmonary vessels may rupture, leading to haemoptysis or epistaxis. There is a tendency for signs to only manifest during exercise, and so patients with a sedentary lifestyle may never show overt disease. Right-sided congestive heart failure may ensue when worm burden is high, and signs can include jugular disension, ascites, marked exercise intolerance and hepatomegaly. A systolic murmur is sometimes audible on cardiac auscultation.

A classification system for the presentation of heartworm disease exists, outlined in the table below.

Class	Clinical Signs
Class 1 |Asymptomatic or mild disease. Weight loss, reduced exercise tolerance or an occasional cough may be seen, No radiographic signs or laboratory abnormalities.
Class 2	Moderate disease. Animal coughs occasionally ahd shows mild-to-moderate exercise intolerance. Lung sounds may be increase, and radiography may show mild-to-moderate changes, e.g. right ventricular enlargement. Anemia and proteinuria may be present.
Class 3	Severe disease. Signs are variable but may include weight loss, exercise intolerance, tachypnoea, dyspnoea, severe/persistent coughing, hemoptysis, syncope, pr ascites. Radiographs appear abnormal: right ventricular hypertrophy, enlargement of the main pulmonary artery, and diffuse pulmonary densities. ECG often shows right ventricular hypertrophy. Aneamia, thrombocytopenia, and proteinuria are seen.
Class 4	Caval syndrome: sudden onset of collapse, haemoglobinuria, and respiratory distress. Usually fatal without immediate surgery.

Caval syndrome represents a severe form of heartworm disease both in dogs and cats. This is characterised by respiratory distress, intravascular haemolysis and haemoglobinuria, signs of right-sided heart failu-e and, frequently, disseminated intrav ascular coagulaktion1.

Although the majority of infected cats are asymptomatic, cases of sudden death without any premonitory clinical signs have been reported. Sometimes, the sudden death is preceded by an acute respiratory crisis, probably due to a parasitic embolism and obstruction of a major pulmonary artery. When present, clinical signs of heartworm disease in cats are generally vague and non-specific. These may include anorexia, lethargy, coughing, vomiting, dyspnoea, syncope and collapse. In some cases, the respiratory signs are very similar to those generally observed in feline asthma.

nfected cats may be asymptomatic or exhibit intermittent coughing, dyspnea, vomiting, lethargy, anorexia, or weight loss. The symptoms often resemble those of feline asthma. In general, signs are most prevalent during periods when worms die, including when young adult worms arrive in the lungs. Antigen tests in cats are negative during the early eosinophilic pneumonitis syndrome, although antibody tests may be positive. Subsequently, clinical signs often resolve and may not reappear for months. Cats harboring mature worms may exhibit intermittent vomiting, lethargy, coughing, or episodic dyspnea. HW death can lead to acute respiratory distress and shock, which may be fatal and appears to be the consequence of pulmonary thrombosis.

Diagnostic Imaging

In dogs, echocardiography is relatively unimportant as a diagnostic tool. Worms observed in the right heart and vena cava are associated with high-burden infection with or without caval syndrome. Severe, chronic pulmonary hypertension causes right ventricular hypertrophy, septal flattening, underloading of the left heart, and high-velocity tricuspid and pulmonic regurgitation. The ECG of infected dogs is usually normal. Right ventricular hypertrophy patterns are seen when there is severe, chronic pulmonary hypertension and are associated with overt or impending right-sided CHF (ascites). Heart rhythm disturbances are usually absent or mild, but atrial fibrillation is an occasional complication in dogs with Class III disease.

In cats, worms can usually be imaged on echocardiography. Parallel hyperechoic lines, which are an image from the heartworm cuticle, may be seen in the right heart and pulmonary arteries. High worm burdens may be associated with worms in the right heart. Echocardiography is more important in cats than dogs because of the increased difficulty of diagnosis and the high sensitivity of the test in experienced hands.

n dogs, thoracic radiography provides the most information on disease severity and is a good screening tool for dogs with clinical signs compatible with dirofilariasis. Class III infections are characterized by a large main pulmonary artery segment and dilated, tortuous caudal lobar pulmonary arteries. If the latter are ≥1.5 times the diameter of the 9th rib at their point of superimposition, then severe pathology is present. Right ventricular enlargement may also be seen. Fluffy, ill-defined parenchymal infiltrates of variable extent often surround the caudal lobar arteries, usually worst in the right caudal lobe, in advanced disease. The infiltrate may improve with cage confinement with or without anti-inflammatory dosages of a corticosteroid. In cats, cardiac changes are less common. The caudal lobar arteries normally appear relatively large, but are larger still with heartworm infection. Patchy parenchymal infiltrates may also be present in cats with respiratory signs. The main pulmonary artery segment usually is not visible due to its relatively midline location.

Laboratory Tests

In addition to special diagnostic tests in both cats and dogs, a CBC, chemistry profile, urinalysis, and particularly thoracic radiographs are indicated. Laboratory data are often normal. Eosinophilia and basophilia are common and together suggest occult dirofilariasis or allergic lung disease. Eosinophilia surges as the L5 arrive in the pulmonary arteries. Subsequently, eosinophil counts vary but are usually high in dogs with immune-mediated occult infections, especially if eosinophilic pneumonitis develops (<10% of total infections). Hyperglobulinemia may be present in dogs and cats due to antigenic stimulation. Hypoalbuminemia in dogs is associated with severe immune-complex glomerulonephritis or right-sided CHF. Serum ALT and alkaline phosphatase are occasionally increased, but do not correlate well with abnormal liver function, efficacy of adulticide treatment, or risk of drug toxicity. Urinalysis may reveal proteinuria that can be semiquantitated by a urine protein:creatinine ratio. Occasionally, severe glomerulonephritis or amyloidosis can lead to hypoalbuminemia and nephrotic syndrome. Dogs with hypoalbuminemia secondary to glomerular disease also lose antithrombin III and are at risk for thromboembolic disease. Hemoglobinuria is associated with Class III disease when RBC are lysed in the pulmonary circulation by fibrin deposition. Heparin therapy (75-100 U/kg, SC, tid) is indicated. Hemoglobinuria is also a classic sign of the vena caval syndrome.

he antigen detection test is the preferred diagnostic method for asymptomatic dogs or when seeking verification of a suspected HW infection. This is the most sensitive diagnostic method available to veterinary practitioners. Even in areas where the prevalence of HW infection is high, ~20% of infected dogs may not be microfilaremic. Also, monthly macrolide prophylaxis induces embryo stasis in female dirofilariae. Available antigen detection tests are very sensitive and specific. To determine when testing might become useful, it is advisable to add a predetection period to the approximate date on which infection may have been possible. A reasonable interval is 7 mo. There is generally no need to test a dog for antigen or microfilariae prior to ~7 mo of age. The level of antigenemia is directly related to the number of mature female worms present. At least 90% of dogs harboring ≥3 adult females will test positive. In general, strong-quick positive reactions correlate with relatively high worm burdens. For low-burden suspects, commercial laboratory-based microwell titer tests are the most sensitive.

Pathology

Dirofilariasis. Courtesy of T. Scase

Dirofilariasis. Courtesy of T. Scase

On post-mortem examination, the right side of the heart is found to be enlarged. There is proliferation of the pulmonary arterial myointima, as well as pulmonary thromboembolism and haemorrhage. If right-sided congestive heart failure was present in life, the hepatomegaly and hepatic congestion will be seen.

Treatment

Adulticidal Treatment

Decisions in the treatment of heartworm disease are dependent on the severity of infection. A scheme exists to classify patients in terms of disease severity². Class one patients have subclinical heartworm disease, and carry an excellent prognosis following treatment wiht adulticidal drugs. Class two animals show mild to moderate clinical signs and similar radiographic changes. These animals may respond positively to treatment. Dogs with class 3 disease have severe clinical signs, such as persistent coughing, dyspnoea, right-sided heart failure or haemoptysis, and these are reflected by severe radiographic signs. These cases have a high risk of pulmonary thromboembolism and so prognosis is guarded and the benefits of adulticidal treatment should be considered carefully.

Even low grade infections in cats may result in pulmonary thromboembolism with adulticidal treatment, and spontaneous remission is seen in some cats. Because of this, symptomatic treatment (cage rest, oxygen supplementation, fluid therapy, bronchodilators and dexamethasone) may be more appropriate in sick cats, and clinically well cats can merely be monitored regularly for remission. Adulticidal treatment should only be considered in cats that fail to respond to supportive treatments but are in a stable condition.

Adulticidal treatment involves the administration of a new generation arsenical compound, melarsomine dihydrochloride (Immiticide, Merial; this product is not licensed for use in the UK). Melarsomine is less nephrotoxic and hepatotoxic than its predecessor thiacetarsamide, and has a higher efficacy. Melarsomine is injected intramuscularly into the lumbar muscles at a recommended dose of 2-5 mg/kg, repeated after 24 hours. However, only a single dose should be administered to class 3 dogs, to kill just a proportion of worms and hence minimise the risk of pulmonary thromboembolism. If the patient remains stable, the standard adulticidal protocol can be administered one month later. In the week following the administration of melarsomine, the likelihood of pulmonary thromboembolism can be minimised with cage rest and corticosteroids at anti-inflammatory doses. If adulticidal treatment is declined by the owner, monthly administration of prophylactic doses of ivermectin may represent a reasonable option because it will prevent further infection and may kill some adult nematodes. Patients with severe caval syndrome may benefit from physical removal of worms from the right side of the heart and the main pulmonary artery using flexible crocodile or basket-type retrieval forceps. This procedure is complex, requires general anaesthesia and fluoroscopic imaging, but may reduce the risk of thromboembolism following subsequent adulticidal treatment.

Microfilaricidal Treatment

No drugs are specifically approved for microfilaricidal treatment of Dirofilaria immitis, and successful elimination of adult worms should results in the demise of circulating microfilariae four to six weeks later². Single doses of ivermectin, milbemycin oxime, moxidection or selamectin are, however, effective at removing microfilariae from the circulation. The sudden death of large numbers of microfilariae may invoke an anaphylactic response, and oral prednisolone may be administered with microfilaricides to help prevent this.

Prevention

Heartworm prophylaxis should be implemented in all cats and dogs living in or visiting areas in which Dirofilaria immitis is endemic. In the UK, milbemycin oxime and selamectin are licensed for the prevention of heartworm disease and should be administered on a monthly basis as they are capable of killing migrating larvae up to week six post-infection. In the event of non-compliance or a missed dose, it may be necessary to test the animal for Dirofilaria immitis six months later if they are likely to have been exposed to infection during the time they were unprotected. Drugs that persist in the long term, such as injectable moxidectin, can help overcome this issue.

Prognosis

In mildly symptomatic or asymptomatic animals, the course of dirofilariasis is usually uneventful following treatment and the prognosis is excellent³. Animals with severe infection carry a guarded prognosis with a higher risk of complications.

References

1. Merck & Co (2008) The Merck Veterinary Manual (Eighth Edition), Merial.
2. Ferasin, L (2004) Disease risks for the travelling pet: Heartworm disease, In Practice, 26(6), 350-357.
3. Tilley, L P and Smith, F W K (2004) The 5-minute Veterinary Consult (Fourth Edition),Blackwell.
4. Ridyard, A (2005) Heartworm and lungworm in dogs and cats in the UK, In Practice, 27(3), 147-153.
5. Venco, L (2007) Heartworm (Dirofilaria immitis) disease in cats. Dirofilaria immitis and D. repens in dog and cat and human infections, 126-132.
6. Venco, L (2007) Heartworm (Dirofilaria immitis) disease in dogs. Dirofilaria immitis and D. repens in dog and cat and human infections, 117-125.