Difference between revisions of "Dirofilaria immitis"

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[[Image:Dirofilaria immitus.jpg|thumb|right|250px|''Dirofilaria immitis'' - Courtesy of the Laboratory of Parasitology, University of Pennsylvania School of Veterinary Medicine]]
  
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==Description==
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Also known as: '''Heartworm Disease — Dirofilariasis
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[[Image:Dirofilaria immitus.jpg|thumb|right|150px|''Dirofilaria immitus'' - Courtesy of the Laboratory of Parasitology, University of Pennsylvania School of Veterinary Medicine]]
 
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[[Image:dirofilariasis.jpg|right|thumb|125px|<small><center>'''Dirofilariasis'''. Courtesy of T. Scase</center></small>]]
 
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[[Image:dirofilariasis 2.jpg|right|thumb|125px|<small><center>'''Dirofilariasis'''. Courtesy of T. Scase</center></small>]]
 
  
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Dirofilaria immitis is a nematode parasite that causes heartworm disease in dogs and, less commonly, cats and ferrets. Heartworm
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Beware confusing with: ''[[Angiostrongylus vasorum]]'', [[angiostrongylosis]].
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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.
 
  
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Infected mosquitos are capable of transmitting HW infections to humans, but there are no reports of such infections becoming patent. Maturation of the infective larvae may progress to the point where they reach the lungs, become encapsulated, and die. The dead larvae precipitate granulomatous reactions called “coin lesions,” which are medically significant because radiographically they appear similar to metastatic lung cancer.
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==Introduction==
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HW infection rates in other companion animals such as ferrets and cats tend to parallel those in dogs in the same geographic region, but usually at a lower prevalence. No age predilection has been reported in ferrets or cats, but male cats have been reported to be more susceptible than females. Indoor and outdoor ferrets and cats can be infected. Other infections in cats, such as those caused by the feline leukemia virus or feline immunodeficiency virus, are not predisposing factors.
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''Dirofilaria immitis'' is a nematode parasite that causes heartworm disease in dogs, cats and ferrets. Heartworm disease is transmitted by [[Culicidae|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. Heartworm disease has been reported in many countries with temperate climate 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.
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''Dirofilaria'' does have zoonotic potential: infected mosquitos can transmit ''D. 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 important because they may be confused with neoplastic metastasis to the lungs on radiography<sup>1</sup>.
  
 
==Life Cycle==
 
==Life Cycle==
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Mosquito vector species acquire the first stage larvae (microfilariae) while feeding on an infected host. Development of microfilariae to the second larval stage (L2) and to the infective third stage (L3) occurs within the mosquito in ~1-4 wk, depending on environmental temperatures. This development phase requires the shortest time when the ambient temperature is >86°F (30°C). When mature, the infective larvae migrate to the labium of the mosquito. As the mosquito feeds, the infective larvae erupt through the tip of the labium with a small amount of hemolymph onto the host’s skin. The larvae migrate into the bite wound, beginning the mammalian portion of their life cycle. A typical Aedes  mosquito is only capable of surviving the developmental phase of small numbers of HW larvae, usually <10 larvae per mosquito.
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''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 25cm<sup>1</sup>. 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. Mosquitoes 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&deg;C takes around 8 days, but when temperatures are down to 18&deg;C, this takes around one month<sup>2</sup>. Below 14&deg;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.  
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In canids and other susceptible hosts, infective larvae (L3) molt into a fourth stage (L4) in 2-3 days. After remaining in the subcutaneous tissue for close to 2 mo, they molt into young adults (L5) that migrate through host tissue, arriving in the pulmonary arteries ~50 days later. Adult worms (males ~15 cm in length, females ~25 cm) develop primarily in the pulmonary arteries of the caudal lung lobes over the next 2-3 mo. They reside primarily in the pulmonary arteries but can move into the right ventricle when the worm burden is high. Microfilariae are produced by gravid females ~6-7 mo postinfection.
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Microfilariae are usually detectable in infected canids not receiving macrolide prophylaxis. However, 25% to >50% of infected canids may not have circulating microfilariae. Thus, the number of circulating microfilariae does not necessarily correlate strongly to adult female HW burden. Adults typically live 3-5 yr, while microfilariae may survive for 1-2 yr while awaiting a mosquito intermediate host.
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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.  
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Most dogs are highly susceptible to HW infection, and the majority of infective larvae (L3) develop into adults. Ferrets are susceptible hosts, and cats are somewhat resistant. A lower percentage of exposed cats develop adult infections and the burden is often only 1-3 worms. Further evidence of relative resistance in cats is the short survival time of many L5 in the pulmonary arteries; adult worms probably survive no longer than 2 yr. Aberrant migration into different organs, including the CNS, has been described in cats.
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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 low<sup>1</sup>. L5 in the pulmonary arteries also have a relatively short (2 year) survival time in cats.
  
 
==Pathogenesis==
 
==Pathogenesis==
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The severity of cardiopulmonary pathology in dogs is determined by worm numbers, host immune response, duration of infection, and host activity level. Live adult HW cause direct mechanical irritation of the intima and pulmonary arterial walls, leading to perivascular cuffing with inflammatory cells, including infiltration of high numbers of eosinophils. Live worms seem to have an immunosuppressive effect; however the presence of dead worms leads to immune reactions and subsequent lung pathology in areas of the lung not directly associated with the dead HW. Longterm infections, due to all of the factors noted (ie, direct irritation, worm death, and immune response) result in chronic lesions and subsequent scarring. Active dogs tend to develop more pathology than inactive dogs for any given worm burden. Frequent exertion increases pulmonary arterial pathology and may precipitate overt clinical signs, including congestive heart failure (CHF). High worm burdens are most often the result of infections acquired from numerous mosquito exposures. High exposures in young, naive dogs in temperate climates can result in severe infections, causing a vena caval syndrome the following year. In general, due to the worm size and smaller dimensions of the pulmonary vasculature, small dogs do not tolerate infections and treatment as well as large dogs.
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Heartworm disease primarily affects the cardiopulmonary system and the severity and extent of lesions depends on several factors. These include the number and location of adult worms<sup>1, 2</sup>, the duration of infection, and the level of activity of the host<sup>1</sup>. 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 an increase in the permeability of pulmonary vessels, giving periarterial oedema and intersitial and alveolar infiltrates. Eventually, irreversible interstitial fibrosis arises.
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HW-associated inflammatory mediators that induce immune responses in the lungs and kidneys (immune complex glomerulonephritis) cause vasoconstriction and possibly bronchoconstriction. Leakage of plasma and inflammatory mediators from small vessels and capillaries causes parenchymal lung inflammation and edema. Pulmonary arterial constriction causes increased flow velocity, especially with exertion, and resultant shear stresses further damage the endothelium. The process of endothelial damage, vasoconstriction, increased flow velocity, and local ischemia is a vicious cycle. Inflammation with ischemia can result in irreversible interstitial fibrosis.
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Pulmonary arterial pathology in cats and ferrets is similar to that in dogs, although the small arteries develop more severe muscular hypertrophy. Arterial thrombosis is caused by both blood clots and worms lodged within narrow lumen arterioles. In cats, parenchymal changes associated with dead HW differ from those observed in dogs and ferrets. Rather than type I cellular edema and damage as found in dogs, cats experience type II cellular hyperplasia, which causes a significant barrier to oxygenation. Most significantly, due to restricted pulmonary vascular capacity and subsequent pathology, both ferrets and cats are more likely to die as a result of HW infection
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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|disseminated intravascular coagulation]]. Due to the smaller numbers of adult worms, caval syndrome is less common in cats<sup>2</sup>.
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In cats, heartworm disease generally causes a diffuse pulmonary infiltrate and an eosinophilic pneumonia<sup>2</sup>. 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==
 
==Signalment==
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''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<sup>1, 3</sup>. In cats, there are no breed or age predispositions, but males are more frequently affected<sup>3</sup>. Ferrets may also contract dirofilariasis; there are no age or sex predilections<sup>1</sup>.
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==Diagnosis==
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===Clinical Signs===
  
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The risk of Dirofilaria immitis infection is greatest in outdoor dogs and cats. Animals of any age may be affected, but infections are most common in 3 to 8 year old dogs. Medium and large breeds are predisposed.
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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 six months after the end of the high-risk season<sup>3</sup>. Therefore, positive laboratory testing may be the first indication of disease<sup>1</sup>. 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 parasite<sup>2</sup>. 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 distension, ascites, marked exercise intolerance and hepatomegaly. A systolic murmur is sometimes audible on cardiac auscultation.
  
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==Diagnosis==
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A classification system for the presentation of heartworm disease exists<sup>1</sup>, outlined in the table below.
  
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'''Diagnosis''':
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{| class="wikitable collapsible"
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*Physical examination:
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|-
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**signs of heart disease
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!width="8%"|<center><u>'''Class '''</u></center>
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**lung involvement
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!width="92%"|<center><u>'''Clinical Signs'''</u></center>
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*Radiography:
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|-
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**enlargement of right heart, main pulmonary arteries; arteries in lung lobes with thickening and tortuosity; inflammation in surrounding tissues
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|<center>'''Class I'''</center> 
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*ECG:
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|'''Asymptomatic or mild disease'''  
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**right axis deviation → deep S waves
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*Weight loss, reduced exercise tolerance or an occasional cough may be seen.
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*Echocardiography:
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*No radiographic signs or laboratory abnormalities.
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**if post caval syndrome suspected - right ventricular enlargement with worms in ventricle appearing as parallel lines.
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|-
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|<center>'''Class II'''</center>
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|'''Moderate disease'''
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*Animal coughs occasionally and shows mild-to-moderate exercise intolerance.
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*Lung sounds may be increased
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*Radiography may show mild-to-moderate changes, e.g. right ventricular enlargement.
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*Anaemia and proteinuria may be present.
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|-
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|<center>'''Class III'''</center>
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|'''Severe disease'''
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*Signs are variable but may include weight loss, exercise intolerance, tachypnoea, dyspnoea, severe/persistent coughing, haemoptysis, syncope, or ascites.
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*Radiographs appear abnormal: right ventricular hypertrophy, enlargement of the main pulmonary artery, and diffuse pulmonary densities. ECG often shows right ventricular hypertrophy.
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*Anaemia, thrombocytopenia, and proteinuria are seen.
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|-
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|<center>'''Class IV'''</center>
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|'''Caval syndrome'''
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*Sudden onset of collapse, haemoglobinuria, and respiratory distress.
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*Usually fatal without immediate surgery.
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|-
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|}
  
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'''Clinical pathology''':
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'''Caval syndrome''' is a very severe form of heartworm disease that can occur in dogs and cats. It is characterised by respiratory distress, signs of right-sided heart failure, intravascular haemolysis and haemoglobinuria. Disseminated intravascular coagulation frequently occurs, and the syndrome is often fatal.
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*needed alongside physical examination and other tests to determine treatment strategy and prognosis.
 
  
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'''Parasite detection''':
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In cats, most infections are asymptomatic. However, sudden death can occasionally occur. This may be preceded by an acute respiratory crisis, thought to be due to parasitic thromboembolism and obstruction of a major pulmonary artery<sup>1, 2</sup>. When clinical signs are less acute, they are vague and may include anorexia, weight loss and lethargy. Intermittent coughing and dyspnoea can appear similar to feline asthma. Syncope may also occur, and cats may vomit. The cause of this vomiting is undetermined<sup>3</sup>.
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*methods for demonstrating microfilariae in blood:
 
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**wet blood smear (okay for quick look, but insensitive) = ''D. immitis'' not progressively motile
 
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**Knott's test = red blood cells lysed; stained sediment examined
 
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**micropore filter = blood forced through; microfilariae held on filter; stained and examined
 
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**antibody detection ELISA = not reliable in dogs, but it is the best for cats (although some false positives)
 
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**antigen detection ELISA (using specific antigen from adult female worm) = reliable positives from 5-7months post-infection in dogs; although occasional false negatives occur → '''not''' useful for cats
 
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*the immunochromatographic test (ICT) uses coloured gold colloidal particles tagged to monoclonal antibodies to visualise the presence of adult worm antigen - performance similar to antigen detection ELISA, but quicker and easier to do (but not as quantitative as some ELISAs are)
 
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*operator error can give false positives, therefore best to confirm result with another test.
 
  
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===Clinical Signs===
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===Radiography===
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In dogs, thoracic radiography provides good information on disease severity and is useful for screening dogs showing clinical signs compatible with ''D. immitis'' infection<sup>1</sup>. However, thoracic radiograph do not necessarily reflect the current worm burden: radiographic signs of advanced disease can persist long after an infection has run its course<sup>4</sup>. Conversely, dogs with high burdens may be inactive and thus show few clinical signs or radiographic changes. Radiographic signs are mild-to-moderate in class II disease, but become more obvious in class III infections. The main pulmonary artery is enlarged<sup>1, 4</sup>, and the caudal lobar vessels appear tortuous<sup>1</sup>. Ill-defined, fluffy infiltrates are apparent, and often surround the caudal lobar vessels. Right-sided cardiomegaly may be appreciated, and pleural and peritoneal effusions can be noted in right-sided congestive heart failure<sup>4</sup>.
  
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In dogs, infection should be identified by serologic testing prior to the onset of clinical signs; however, it should be kept in mind that HW antigenemia and microfilaremia do not appear until ~5 and 6.5 mo postinfection, respectively. When dogs are not administered a preventative and are not appropriately tested, clinical signs such as coughing, exercise intolerance, unthriftiness, dyspnea, cyanosis, hemoptysis, syncope, epistaxis, and ascites (right-sided CHF) are likely to develop. The frequency and severity of clinical signs correlate to lung pathology and level of patient activity. Signs are often not observed in sedentary dogs, even though the worm burden may be relatively high. Infected dogs experiencing a dramatic increase in activity, such as during hunting seasons, may develop overt clinical signs. Canine HW disease can be classified by physical examination, thoracic radiographs, urinalysis, and PCV. Class I is asymptomatic to mild HW disease, with no clinical or radiographic signs and no laboratory abnormalities. Subjective signs such as loss of condition, decreased exercise tolerance, or occasional cough might be seen. Class II is moderate HW disease, characterized by an occasional cough and mild-to-moderate exercise intolerance. A slight loss of condition, increased lung sounds, and mild to moderate radiographic changes, such as right ventricular enlargement, are present. Laboratory results may show anemia and proteinuria. Class III is severe disease variably characterized by anemia, weight loss, exercise intolerance, tachypnea at rest, severe or persistent coughing, dyspnea, hemoptysis, syncope, and ascites. Severely abnormal radiographs may show right ventricular hypertrophy, enlargement of the main pulmonary artery, and diffuse pulmonary densities. Laboratory results indicate marked anemia, thrombocytopenia, and proteinuria. Electrocardiographic evidence of right ventricular hypertrophy is often present. Class IV, also known as the caval syndrome, is characterized by sudden onset with collapse, hemoglobinuria, and respiratory distress. If surgery is not immediately instituted, this syndrome is usually fatal.
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Cardiac changes on thoracic radiography are less common in cats than dogs. The caudal lobar veins are enlarged (greater than 1.5 times the width of the ninth rib), and the pulmonary arteries are blunted and tortuous<sup>3, 5</sup>. Patchy parenchymal infiltrates may be seen in the region of vessels in animals showing respiratory signs<sup>1, 3</sup>. Enlargement of the main pulmonary artery cannot normally be seen in cats, as it has a relatively midline position and is thus obscured by the cardiac silhouette<sup>1, 5</sup>. Right-sided cardiomegaly is not considered a typical finding in the cat<sup>5</sup>.
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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.
 
  
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===Diagnostic Imaging===
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===Echocardiography===
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In dogs, echocardiography is not particularly useful as a diagnostic tool for heartworm disease. In severe, chronic pulmonary hypertension, right ventricular hypertrophy, septal flattening, underloading of the left heart, and high-velocity tricuspid and pulmonic regurgitation may be seen<sup>1</sup>. With caval syndrome or high-burden infections, worms may be visualised in the right heart and vena cava.
  
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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.
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Echocardiography is more important in cats than dogs because of the increased difficulty of diagnosis and the fact that this test can have a high sensitivity depending on operator experience<sup>1</sup>. Specificity is 100%<sup>5</sup>, and the test can help exclude or confirm other primary cardiac diseases such as hypertrophic cardiomyopathy<sup>3</sup>. Worms can be visualised as parallel hyperechoic lines<sup>1</sup>, and are seen in the right atrium and ventricle and main pulmonary artery<sup>1, 3, 5</sup>.
  
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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.  
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===Electrocardiography===
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The ECG of infected dogs is usually normal. Right ventricular hypertrophy patterns may be seen in chronic ,severe pulmonary hypertension and are associated with impending or apparent right-sided congestive heart failure<sup>4</sup>. Arrhythmias do not normally occur, buy atrial fibrillation is is occasionally seen in Class III disease.
  
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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.
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Electrocardiography is less useful in the cat, as involvement of the heart chambers does not occur as frequently as in the dog<sup>5</sup>.
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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===
 
===Laboratory Tests===
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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).
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In both dogs and cats, '''routine haematology, biochemistry and urinalysis''' should be performed. Most parameters are usually within normal limits, but an anaemia can often be seen. Eosinophilia and basophilia are also common<sup>1, 3</sup>. Eosinophilia peaks as L5 enter the pulmonary arteries and subsequently varies. An inflammatory leukogram is possible<sup>3</sup>. Hyperglobulinaemia due to antigenic stimulation is an inconsistent finding<sup>1, 3</sup>. Right-sided heart failure or immune-complex glomerulonephritis can lead to hypoalbuminaemia and, very occasionally, nephrotic syndrome<sup>1</sup>. Because of this, it is possible for urinalysis to reveal proteiunuria<sup>1, 3</sup>. Haemoglobinaemia and haemoglobinuria are associated with caval syndrome<sup>3</sup>.
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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.  
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[[Image:dirofilariasis.jpg|right|thumb|200px|Dirofilariasis. Courtesy of T. Scase]]
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There are several methods for the specific demonstration of ''Dirofilaria immitis'' in the animal. Firstly, direct '''microscopic examination''' allows rapid identification of microfilariae in a drop of fresh blood, as their movements can vigorously displace the surrounding red blood cells<sup>2</sup>. Despite being quick, simple and inexpensive, this test is not sufficiently sensitive to provide a definitive diagnosis, particularly when there is a low concentration of microfilariae in the bloodstream. '''Filtration methods''' therefore exist to facilitate the microscopic demonstration of microfilariae<sup>2, 3</sup>. These include the '''modified Knott's test''', which involves haemolysis, centrifugation and staining with methylene blue before direct examination. Tests such as this are more sensitive than merely examining a drop of blood, and the morphology of microfilariae can be clearly seen. However, sensitivity in comparison to other methods is still low and so microfilarial identification tests are often reserved for confirmation of weak positive antigen tests and determination of microfilarial status prior to treatment with a microfilaricide<sup>3</sup>. Cats frequently lack circulating microfilariae, and so direct microscopic examination is of little use in this species.
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[[Image:dirofilariasis 2.jpg|right|thumb|200px|'''Dirofilariasis'''. Courtesy of T. Scase]]
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Tests exist to detect ''D. immitis'' antigens. '''ELISAs''' specific for proteins released from the reproductive tract of adult female worms are available for in-house use<sup>2</sup>. Sensitivity and specificity are excellent, but small worm burdens and the presence of immature female- or male-only infections can give low antigen titres hence false negatives. This is especially common in cats. '''Specific agglutination and immunochromatography''' techniques are also available for use in dogs. Any antigen test performed in the first six months of infection may give false negative results as levels of circulating antigen are initially low while female worms mature. '''In-house tests''' are also available to detect antibody against ''Dirofilaria immitis''. The presence of antibodies confirms exposure, but does not necessarily provide information about current infection. These tests are therefore most useful for ruling out infection. ''D. immitis'' antibody tests have a low specificity<sup>2</sup> and so have largely been superceded by tests for antigen.
  
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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.
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'''PCR-based tests''' are highly sensitive and specific for the diagnosis of immature and adult heartworms, and are especially useful in unconventional (e.g. wildlife) hosts<sup>2</sup>. At present, these tests are not widely available for the diagnosis of ''Dirofilaria immitis''.
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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===
 
===Pathology===
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'''Worms produce''':
 
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*substances that are:
 
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**antigenic
 
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**immunomodulatory
 
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**pharmacologically active.
 
  
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'''Lesions are''':
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On post-mortem examination, ''Dirofilaria immitis'' worms are apparent in the pulmonary artery and possibly the right side of the heart. The right side of the heart is found to be enlarged and there is proliferation of the pulmonary arterial myointima. Pulmonary thromboembolism and haemorrhage may be seen. If right-sided congestive heart failure was present in life, hepatomegaly and hepatic congestion will be apparent.
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*'''not''' confined to the location of the worms
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*also caused by shear stress of high blood flow.
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==Treatment==
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Animals with right-sided congestive heart failure require stablisation with diuretics, ACE inhibitors and cage rest before treatment for heartworm disease is implemented. Animals with severe respiratory signs also require stabilisation with oxygen supplementation, anti-inflammatory doses of corticosteroid and anti-thrombotic drugs.
 +
 
 +
The specific adulticidal treatment for ''Dirofilaria immitis'' is '''melarsomine dihydrochoride''', a new generation arsenical compound. Melarsomine is administered intramuscularly into the epaxial muscles, and pressure should be applied during and after needle withdrawal<sup>3</sup>. A "graded-kill" protocol is recommended: an initial injection is followed one month later with two injections at an interval of 24 hours, given on opposite sides<sup>1-4</sup>. This spreads the killing effects over two treatments, with an aim to reducing the occurrence of thromboembolism after parasite death. Cage rest and anti-inflammatory doses of corticosteroids in the week following melarsomine treatment can also reduce the likelihood of pulmonary thromboembolism. Antigen testing four months after adulticidal treatment will determine whether it is necessary to repeat the therapy<sup>3</sup>.
 +
 
 +
Adulticidal treatment may be declined by the owner, owing to the risk of thromboembolism. Alternatively, it may not be possible to implement adulticidal treatment if the patient is suffering renal or hepatic failure<sup>3</sup>. In these cases, monthly administration of prophylactic doses of ivermectin is a reasonable treatment option, as it prevents further infection and may kill some adult nematodes<sup>2</sup>.
 +
 
 +
Even low grade infections in cats may result in pulmonary thromboembolism with adulticidal treatment. Because of this, symptomatic treatment of sick cats may be followed by surgical or catheter-based extraction of nematodes once the patient is stable<sup>3</sup>. Stablisation is similar to that for feline asthma, and can include cage rest, oxygen supplementation, bronchodilators (e.g. theophylline), tapering doses of prednisolone, and balanced fluid therapy if indicated<sup>3</sup>. Heartworms have a much shorter life-span in cats, and spontaneous remission is seen in some cases. Regular monitoring may therefore be the best course of action in clinically well cats.
 +
 
 +
In '''caval syndrome''', surgery is the treatment of choice. Worms are removed from the right side of the heart and the main pulmonary artery using flexible crocodile or basket-type retrieval forceps<sup>2</sup>. This procedure is complex and requires general anaesthesia and fluoroscopic imaging, but reduces the risk of thromboembolism following subsequent adulticidal treatment. Symptomatic and supportive therapy to stabilise the patient should be continued for around one month after surgery before adulticidal treatment is administered<sup>3</sup>.
  
−
'''Severity''':
+
'''No drugs are specifically approved for microfilaricidal treatment''' of ''Dirofilaria immitis'', and successful elimination of adult worms should result in the demise of circulating microfilariae four to six weeks later<sup>2</sup>. '''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.
−
*not associated with the number of worms
+
−
*exacerbated by exercise (i.e. by high blood flow rate)
+
Heartworm prophylaxis should be implemented in all cats and dogs living in or visiting areas in which ''Dirofilaria immitis'' is endemic. Ivermectin or milbemycin oxime can be given ''per os'' on a monthly basis, and selemectin spot-on is effective when applied each month. If animals have already been exposed to ''Dirofilaria immitis'' it may be wise to perform an antigen test before starting treatment. In endemic countries, routine antigen testing six months after the end of the previous heartworm season will detect infections that have slipped through the net, and enable treatment during the mild, early stages of disease<sup>3</sup>.
−
*sedentary dogs often asymptomatic - symptoms most commonly associated with racing greyhounds.
 
  
−
'''Acute prepatent disease''':
+
==Prognosis==
−
*immature adult worms in caudal distal pulmonary arteries
 
−
*leads to intense diffuse eosinophilic reaction, which in turn leads to coughing.
 
  
−
'''Chronic disease''':
+
In mildly symptomatic  or asymptomatic animals, the course of dirofilariasis is usually uneventful following treatment and the prognosis is excellent<sup>3</sup>. Animals with severe infection carry a guarded prognosis with a higher risk of complications.
−
*mature worms in right heart and pulmonary arteries
 
−
*endothelial swelling and sloughing
 
−
*increased permeability → inflammation → periarteritis
 
−
*platelets/white blood cells activated → thrombosis
 
−
*proliferation of smooth muscle, thickening of media:
 
  
−
→ impairment of blood flow
+
{{Learning
 +
|literature search = [http://www.cabdirect.org/search.html?rowId=1&options1=AND&q1=%22Dirofilaria+immitis%22&occuring1=title&rowId=2&options2=AND&q2=&occuring2=freetext&rowId=3&options3=AND&q3=&occuring3=freetext&x=21&y=6&publishedstart=2000&publishedend=yyyy&calendarInput=yyyy-mm-dd&la=any&it=any&show=all Dirofilaria immitis publications since 2000]
 +
|full text = [http://www.cabi.org/cabdirect/FullTextPDF/2010/20103181752.pdf '''A review of American heartworm society guidelines for the management of heartworm infections in cats.''' Guerrero, J.; The North American Veterinary Conference, Gainesville, USA, Small animal and exotics. Proceedings of the North American Veterinary Conference, Orlando, Florida, USA, 16-20 January 2010, 2010, pp 1173-1176, 1 ref.]
  
−
→ pulmonary hypertension
+
[http://www.cabi.org/cabdirect/FullTextPDF/2008/20083097550.pdf '''Epidemiology and prevention of ''Dirofilaria'' infections in dogs and cats.''' Genchi, C.; Guerrero, J.; McCall, J. W.; Venco, L.; Veterinary Parasitology and Parasitic Diseases, Naples, Italy, Mappe Parassitologiche, 2007, 8, pp 145-161, many ref.]
  
−
→ right ventricular strain
+
[http://www.cabi.org/cabdirect/FullTextPDF/2006/20063226177.pdf ''' Heartworm of dog - its aetiopathogenesis, diagnosis, treatment and prevention.''' Kundu, P.; Intas Pharmaceuticals Ltd, Ahmedabad, India, Intas Polivet, 2006, 7, 1, pp 106-110, 16 ref.]
  
−
→ right ventricular hypertrophy and right-sided heart failure
+
[http://www.cabi.org/cabdirect/FullTextPDF/2005/20053201370.pdf ''' The utility of echocardiography in the diagnosis of feline heartworm disease: a review of published reports.''' Defrancesco, T. C.; Atkins, C. E.; Seward, R. L.; Knight, D. H.; American Heartworm Society, Batavia, USA, Recent advances in heartworm disease: Symposium '98, Tampa, Florida, USA, 1-3 May, 1998, 1998, pp 103-106, 20 ref.]
−
*insufficient blood pumped through pulmonary capillary bed → insufficient preload for left ventricle.
 
  
−
'''Post Caval Syndrome (Dirofilarial haemoglobinuria)''':
+
|Vetstream = [https://www.vetstream.com/canis/search?s=nematode Nematodes]
−
*can be acute or chronic
+
}}
−
*heavy heartworm infestation:
 
−
**entangled clumps of worms → impaired closure of tricuspid valve → post-caval stagnation → hepatic congestion and hepatic failure
 
−
*this is accompanied by increased red blood cell fragility, haemolytic anaemia and haemolobinuria.
 
  
−
==Treatment==
 
−
Treatment in Dogs:
 
−
The extent of the preadulticide evaluation will vary depending on the clinical status of the patient and the likelihood of coexisting diseases that may affect the outcome of treatment. Clinical laboratory data should be collected selectively to complement information obtained from a thorough history, physical examination, antigen test, and usually thoracic radiography.
 
−
The most important variables influencing the probability of postadulticide thromboembolic complications and the outcome of treatment are the extent of concurrent pulmonary vascular disease and the severity of infection. Assessment of cardiopulmonary status is indispensable for evaluating a patient’s prognosis. Postadulticide pulmonary thromboembolic complications are most likely to occur in heavily infected dogs already exhibiting clinical and radiographic signs of severe pulmonary arterial vascular obstruction, especially if CHF is present.
 
−
The only available heartworm adulticide is melarsomine dihydrochloride, which is effective against mature (adult) and immature heartworms of both genders. For Class I and II patients, melarsomine is given at 2.5 mg/kg, deep IM in the epaxial (lumbar) musculature in the L3-L5 region using a 22 g needle (1 in. long for dogs <10 kg or 1.5 in. for dogs >10 kg). Pressure is applied during delivery and for 1 min after the needle is withdrawn to prevent SC leakage. The procedure is repeated on the opposite side 24 hr later. Approximately one-third of dogs will exhibit local pain, swelling, soreness with movement, or sterile abscessation at the injection site. Local fibrosis is uncommon.
 
−
Dogs with high worm burdens are at risk of severe pulmonary thromboembolism from several days to 6 wk postadulticide. Dogs with Class III infection receive the alternate (split-dose) regimen of 1 injection, followed in 1 mo by 2 injections 24 hr apart. Administration of a single initial dose results in a graded (~50%) worm kill and reduced pulmonary complications. By initially killing few worms and completing the treatment in 2 stages, the cumulative impact of worm emboli on severely diseased pulmonary arteries and lungs can be reduced. This 3-injection protocol is becoming the treatment of choice of many veterinarians regardless of stage of disease, due to its increased safety and efficacy.
 
−
Other treatment protocols recommend the administration of prophylactic doses of ivermectin for 1-6 mo prior to administration of melarsomine, if the clinical presentation does not demand immediate intervention. The rationale for this approach is to greatly reduce or eliminate circulating microfilariae and migrating D immitis larvae, stunt immature HW, and reduce female worm mass by destroying the reproductive system. This results in reduced antigenic mass, which in turns reduces the risk of pulmonary thromboembolism.
 
−
Following melarsomine injection, exercise must be severely restricted for 4-6 wk to minimize thromboembolic lung complications. A low cardiac output should be maintained in order to reduce thrombosis and endothelial damage and facilitate lung repair. Adverse effects of melarsomine are otherwise limited to local inflammation, brief low-grade fever, and salivation. Hepatic and renal toxicity are seldom seen.
 
−
Class III patients should be stabilized prior to melarsomine administration. Stabilizing treatment variably includes cage confinement, oxygen, corticosteroids, and heparin (75-100 U/kg, SC, tid) for 1 wk prior to the alternate melarsomine treatment protocol.
 
−
Patients with right-sided CHF should be treated with furosemide (1-2 mg/kg, bid), a low-dose angiotensin-converting enzyme (ACE) inhibitor such as enalapril (0.25 mg/kg, bid, possibly increased to 0.5 mg/kg, bid after 1 wk pending renal function test results), and a restricted sodium diet. Digoxin, digitoxin, and arteriolar dilators, such as hydralazine and amlodipine, should not be administered. Digoxin is not effective for cor pulmonale; arteriolar dilators, and occasionally even ACE inhibitors, are likely to cause systemic hypotension.
 
−
Postadulticide thromboembolic complications can occur 2-30 days following treatment, with signs most likely 14-21 days after treatment. Clinical signs are coughing, hemoptysis, dyspnea, tachypnea, lethargy, anorexia, and fever. Laboratory findings may include an inflammatory leukogram, thrombocytopenia, and prolonged activated clotting time or prothrombin time. A postinjection increase in serum CK may be noted. Local or disseminated intravascular coagulopathy may occur when platelet counts are <100,000/µL. Treatment for severe thromboembolism should include oxygen, cage confinement, a corticosteroid at an anti-inflammatory dosage (eg, prednisone at 1.0 mg/kg, PO, sid), and low-dose heparin (75-100 U/kg, SC, tid) for several days to 1 wk. Most dogs respond within 24 hr. Severe lung injury is likely if, after 24 hr of oxygen therapy, no improvement is noted and partial pressures of oxygen remain <70 mm Hg.
 
−
Both the standard melarsomine protocol and the alternate regimen kill all or most worms in ~75% of dogs. Antigen testing is performed 6 mo after the first 2 doses of the standard protocol or 4-6 mo after the third dose of the alternate protocol. A positive test result should be followed by retreatment (2 injections, 24 hr apart) if the antigen test is strongly positive, if the patient is still symptomatic, and if the patient is an athlete or a working dog. Mild infection, a weakly positive antigen test, absence of clinical signs, advanced age, and a sedentary dog are factors that may negate the need for a repeat melarsomine treatment. Maintaining dogs on ivermectin/pyrantel pamoate to slowly kill residual worms over the following 20 mo is an alternative in nonperforming dogs with a post-melarsomine weakly positive antigen test result.
 
−
Ivermectin/pyrantel pamoate administered monthly for ~2 yr beginning at 5-7 mo post-L3 inoculation eradicates most adult worms. Further, during this time period, some older worms are also killed. However, the use of ivermectin/pyrantel pamoate is seldom a substitute for melarsomine treatment because the slow kill may allow pulmonary pathology to progress in the interim.
 
−
In caval syndrome cases (class IV), surgical removal of worms from the right atrium and orifice of the tricuspid valve is necessary to save the life of the dog. This may be accomplished by using local anesthesia and either a rigid or flexible alligator forceps, or an intravascular retrieval snare, introduced preferentially via the right external jugular vein. With fluoroscopic guidance, if available, the instrument should continue to be passed until worms can no longer be retrieved. Immediately following a successful operation, the clinical signs should lessen or disappear. Fluid therapy may be necessary in critically ill, hypovolemic dogs to restore hemodynamic and renal function. Within a few weeks following recovery from surgery, adulticide chemotherapy is recommended to eliminate any remaining worms, particularly if many are still visible echocardiographically.
 
−
Microfilaricide Treatment:
 
−
At specific preventive dosages, the macrolide preventative drugs are effective microfilaricides, although not approved by the FDA for this purpose. Adverse reactions may occur in dogs with high microfilarial counts (>40,000/µL), depending on the type of macrolide given. However, the microfilarial count is usually lower, and mild adverse reactions occur in ~10% of dogs. Most adverse reactions are limited to brief salivation and defecation, occurring within hours and lasting up to several hours. Dogs, especially small dogs (<10 kg), with high microfilarial counts (>40,000/µL) may develop tachycardia, tachypnea, pale mucous membranes, lethargy, retching, diarrhea, and even shock. Treatment includes IV balanced electrolyte solution and a soluble corticosteroid. Recovery is usually rapid when treatment is administered quickly. Microfilarial counts are not routinely performed, and thus severe reactions are seldom expected. Treatment specifically targeting circulating microfilariae may be started as early as 3-4 wk following adulticide administration. More commonly, microfilariae are eventually eliminated, even from non-adulticide-treated dogs, after several months of treatment with prophylactic doses of the macrocyclic lactones. No drugs are currently approved as microfilaricides by the FDA. However, licensed veterinarians are permitted extra-label use of certain drugs if a valid veterinarian-client-patient relationship exists. The use of monthly administered HW chemoprophylactics as microfilaricides is governed by this regulation. The macrocyclic lactones are the safest and most effective microfilaricidal drugs available. Livestock preparations of these drugs should not be used to achieve higher doses for the purpose of obtaining more rapid results. The macrolide of choice for killing microfilariae quickly is milbemycin (0.5 mg/kg, PO, 1 dose). Performance of a microfilariae test is recommended at the time the antigen test is performed (6 mo after the adulticide treatment).
 
−
Developing Larvae:
 
−
Ivermectin/pyrantel pamoate, administered monthly for 1 yr to dogs with larvae that are no more than 4 mo post-L3 inoculation, prevents the development of infection. Continuous monthly administration of prophylactic doses of ivermectin, alone or in combination with pyrantel pamoate, is also highly effective against late precardiac larvae and young (<7 mo postinfection) quasi-adult HW. Comparable capability of the other macrocylic lactones has not been reported. This extended protection is important in dogs of unknown medical history that may have acquired HW infections because of lack of preventive drug administration or lack of compliance.
 
−
Back to top
 
−
Treatment in Cats:
 
−
There is currently no satisfactory treatment approach to heartworm infections in cats. Infection often is lethal, and a safe and effective melarsomine protocol has not yet been developed. Thus, all cats in canine HW-endemic regions should receive drug prophylaxis. The adult heartworm lifespan in cats is probably ≤2 yr, so spontaneous recovery is possible. Cats may remain asymptomatic, experience episodic vomiting and/or episodic dyspnea (resembling asthma), may die suddenly from pulmonary thromboembolism, or rarely, develop CHF. With each worm death, pulmonary complications occur. There does not appear to be an association between the presence, absence, or severity of clinical signs and the likelihood of acute complications.
 
−
Many cats are managed conservatively with restricted activity and corticosteroid therapy, such as prednisolone (1.0-2.0 mg/kg, PO, every 24-48 hr). Steroids reduce the severity of vomiting and respiratory signs. The hope is that episodes of pulmonary complications will not prove fatal as the worms die. Barring superinfection, 25-50% of cats may survive with this approach. Serial antibody testing (at 6-mo intervals) can be used to monitor status.
 
−
Surgical retrieval of worms from the right atrium, right ventricle, and vena cavae via jugular venotomy can be attempted in patients with high worm burdens detected by echocardiography. An endoscopic basket or horsehair brush can be advanced via the right jugular vein under fluoroscopy.
 
−
Back to top
 
  
−
==Prevention==
+
{{Chapter}}
−
Heartworm infection is completely preventable with macrolide prophylaxis. Preventive therapy in dogs is recommended beginning at 6-8 wk of age. No testing is necessary at this age. When started at ~1 yr of age, an antigen test is recommended. Before starting a prophylactic regime, all mature dogs that may have been infected >7 mo earlier should be antigen tested and, in appropriate instances, tested for presence of microfilariae. The determination of HW status before starting chemoprophylaxis will avoid unnecessary delay in detecting subclinical infections, and potential confusion concerning effectiveness of the preventive program, if a pre-existing infection becomes evident after beginning chemoprophylaxis. Year-round prevention is advised, but in northern climates, chemoprophylaxis is often initiated in the spring and continued through November. Year-round macrolide administration will arrest the development of larval stages (L3 and L4) that might have occurred prior to preventative initiation or when monthly doses were missed.
+
{{Mansonchapter
−
The macrolide preventives ivermectin, milbemycin oxime, moxidectin, and selamectin are safe and effective as prescribed for all breeds. Ivermectin/pyrantel pamoate (hookworms and roundworms) and milbemycin (hookworms, roundworms, and whipworms) also provide control of intestinal nematodes. Milbemycin, however, kills microfilariae (L1) quickly and shock can occur in the face of high microfilarial concentrations. Thus, milbemycin is not administered as a preventive in dogs with microfilariae. Selamectin is administered topically at a monthly dosage of ~6 mg/kg and also kills adult fleas and prevents flea eggs from hatching for 1 mo. It also is indicated for the treatment and control of Otodectes cynotis in dogs and cats, sarcoptic mange, Dermacentor variabilis infestations in dogs, Ancylostoma tubaeforme , and Toxocara cati in cats.
+
|chapterlink = http://www.mansonpublishing.co.uk/book-images/9781840760576_sample.pdf
−
Annual antigen testing is recommended because overall owner compliance with macrolide prophylaxis is only ~50%. The injectable form of moxidectin is effective for at least 6 mo following 1 injection but use in microfilaremic dogs is not advised. At the time of publication, this formulation was not available in the USA because of concerns regarding toxicity in dogs. With macrolide administration for 6 mo and longer, microfilariae production by female worms ceases and antigen testing is required for detection of infection.
+
|chaptername = Cardiopulmonary Dirofilariasis
−
Heartworm prevention is recommended for all cats in endemic regions, regardless of housing status, because of the potential severe consequences. Ivermectin for cats is safe and effective at 25 µg/kg, PO, once monthly. At this dose, the formulation is also effective against Ancylostoma tubaeforme and A braziliense . Preventive treatment should be initiated in all adult cats, in kittens 6 wk of age, and continued lifelong. Annual antigen and antibody testing is of limited value in cats receiving prophylaxis.
+
|book = Arthropod-borne Infectious Diseases of the Dog and Cat
 +
|author = Susan E. Shaw, Michael J. Day
 +
|isbn = 9781840760576
 +
}}
  
−
==Prognosis==
 
 
==Links==
 
==Links==
 +
 +
*[http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/11300.htm The Merck Veterinary Manual - Heartworm Disease]
 +
*[http://www.dogheartworm.org/ dogheartworm.org]
 +
*[http://www.defra.gov.uk/foodfarm/farmanimal/diseases/vetsurveillance/dactari/ DEFRA - Dog and Cat Travel and Risk Information]
 +
 
==References==
 
==References==
  
 
#Merck & Co (2008) '''The Merck Veterinary Manual (Eighth Edition)''', ''Merial''.
 
#Merck & Co (2008) '''The Merck Veterinary Manual (Eighth Edition)''', ''Merial''.
−
#Ridyard, A (2005) Heartworm and lungworm in dogs and cats in the UK, ''In Practice'', '''27(3)''', 147-153.
 
 
#Ferasin, L (2004) Disease risks for the travelling pet: Heartworm disease, ''In Practice'', '''26(6)''', 350-357.
 
#Ferasin, L (2004) Disease risks for the travelling pet: Heartworm disease, ''In Practice'', '''26(6)''', 350-357.
 +
#Tilley, L P and Smith, F W K (2004) '''The 5-minute Veterinary Consult (Fourth Edition)''',''Blackwell''.
 +
#Venco, L (2007) Heartworm (Dirofilaria immitis) disease in dogs. ''Dirofilaria immitis and D. repens in dog and cat and human infections'', 117-125.
 
#Venco, L (2007) Heartworm (Dirofilaria immitis) disease in cats. ''Dirofilaria immitis and D. repens in dog and cat and human infections'', 126-132.
 
#Venco, L (2007) Heartworm (Dirofilaria immitis) disease in cats. ''Dirofilaria immitis and D. repens in dog and cat and human infections'', 126-132.
−
#Venco, L (2007) Heartworm (Dirofilaria immitis) disease in dogs. ''Dirofilaria immitis and D. repens in dog and cat and human infections'', 117-125.  
+
#Ridyard, A (2005) Heartworm and lungworm in dogs and cats in the UK, ''In Practice'', '''27(3)''', 147-153.
 +
 
 +
 
 +
{{review}}
 +
 
 +
==Webinars==
 +
<rss max="10" highlight="none">https://www.thewebinarvet.com/parasitology/webinars/feed</rss>
  
 
[[Category:Filarioidea]]
 
[[Category:Filarioidea]]
 
[[Category:Dog_Nematodes]]
 
[[Category:Dog_Nematodes]]
 
[[Category:Cat_Nematodes]]
 
[[Category:Cat_Nematodes]]
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[[Category:To_Do_-_Parasites]]
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[[Category:Zoonoses]]
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[[Category:Cardiovascular Diseases - Dog]]
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[[Category:Cardiovascular Diseases - Cat]]
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[[Category:Respiratory Parasitic Infections]]
  
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[[Category:Respiratory Parasitic Infections]]
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[[Category:Expert_Review]]
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[[Category:To_Do_-_Lizzie]]
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[[Category:Cardiology Section]]

Latest revision as of 17:07, 6 January 2023

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

Also known as: Heartworm Disease — Dirofilariasis

Beware confusing with: Angiostrongylus vasorum, angiostrongylosis.

Introduction

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. Heartworm disease has been reported in many countries with temperate climate 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.

Dirofilaria does have zoonotic potential: infected mosquitos can transmit D. 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 important 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. Mosquitoes 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 on several factors. These include the number and location of adult worms1, 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 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-represented1, 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 six months after the end of the high-risk season3. 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 distension, ascites, marked exercise intolerance and hepatomegaly. A systolic murmur is sometimes audible on cardiac auscultation.

A classification system for the presentation of heartworm disease exists1, outlined in the table below.

Class
Clinical Signs
Class I
 Asymptomatic or mild disease
  • Weight loss, reduced exercise tolerance or an occasional cough may be seen.
  • No radiographic signs or laboratory abnormalities.
Class II
 Moderate disease
  • Animal coughs occasionally and shows mild-to-moderate exercise intolerance.
  • Lung sounds may be increased
  • Radiography may show mild-to-moderate changes, e.g. right ventricular enlargement.
  • Anaemia and proteinuria may be present.
Class III
 Severe disease
  • Signs are variable but may include weight loss, exercise intolerance, tachypnoea, dyspnoea, severe/persistent coughing, haemoptysis, syncope, or ascites.
  • Radiographs appear abnormal: right ventricular hypertrophy, enlargement of the main pulmonary artery, and diffuse pulmonary densities. ECG often shows right ventricular hypertrophy.
  • Anaemia, thrombocytopenia, and proteinuria are seen.
Class IV
 Caval syndrome
  • Sudden onset of collapse, haemoglobinuria, and respiratory distress.
  • Usually fatal without immediate surgery.

Caval syndrome is a very severe form of heartworm disease that can occur in dogs and cats. It is characterised by respiratory distress, signs of right-sided heart failure, intravascular haemolysis and haemoglobinuria. Disseminated intravascular coagulation frequently occurs, and the syndrome is often fatal.

In cats, most infections are asymptomatic. However, sudden death can occasionally occur. This may be preceded by an acute respiratory crisis, thought to be due to parasitic thromboembolism and obstruction of a major pulmonary artery1, 2. When clinical signs are less acute, they are vague and may include anorexia, weight loss and lethargy. Intermittent coughing and dyspnoea can appear similar to feline asthma. Syncope may also occur, and cats may vomit. The cause of this vomiting is undetermined3.

Radiography

In dogs, thoracic radiography provides good information on disease severity and is useful for screening dogs showing clinical signs compatible with D. immitis infection1. However, thoracic radiograph do not necessarily reflect the current worm burden: radiographic signs of advanced disease can persist long after an infection has run its course4. Conversely, dogs with high burdens may be inactive and thus show few clinical signs or radiographic changes. Radiographic signs are mild-to-moderate in class II disease, but become more obvious in class III infections. The main pulmonary artery is enlarged1, 4, and the caudal lobar vessels appear tortuous1. Ill-defined, fluffy infiltrates are apparent, and often surround the caudal lobar vessels. Right-sided cardiomegaly may be appreciated, and pleural and peritoneal effusions can be noted in right-sided congestive heart failure4.

Cardiac changes on thoracic radiography are less common in cats than dogs. The caudal lobar veins are enlarged (greater than 1.5 times the width of the ninth rib), and the pulmonary arteries are blunted and tortuous3, 5. Patchy parenchymal infiltrates may be seen in the region of vessels in animals showing respiratory signs1, 3. Enlargement of the main pulmonary artery cannot normally be seen in cats, as it has a relatively midline position and is thus obscured by the cardiac silhouette1, 5. Right-sided cardiomegaly is not considered a typical finding in the cat5.

Echocardiography

In dogs, echocardiography is not particularly useful as a diagnostic tool for heartworm disease. In severe, chronic pulmonary hypertension, right ventricular hypertrophy, septal flattening, underloading of the left heart, and high-velocity tricuspid and pulmonic regurgitation may be seen1. With caval syndrome or high-burden infections, worms may be visualised in the right heart and vena cava.

Echocardiography is more important in cats than dogs because of the increased difficulty of diagnosis and the fact that this test can have a high sensitivity depending on operator experience1. Specificity is 100%5, and the test can help exclude or confirm other primary cardiac diseases such as hypertrophic cardiomyopathy3. Worms can be visualised as parallel hyperechoic lines1, and are seen in the right atrium and ventricle and main pulmonary artery1, 3, 5.

Electrocardiography

The ECG of infected dogs is usually normal. Right ventricular hypertrophy patterns may be seen in chronic ,severe pulmonary hypertension and are associated with impending or apparent right-sided congestive heart failure4. Arrhythmias do not normally occur, buy atrial fibrillation is is occasionally seen in Class III disease.

Electrocardiography is less useful in the cat, as involvement of the heart chambers does not occur as frequently as in the dog5.

Laboratory Tests

In both dogs and cats, routine haematology, biochemistry and urinalysis should be performed. Most parameters are usually within normal limits, but an anaemia can often be seen. Eosinophilia and basophilia are also common1, 3. Eosinophilia peaks as L5 enter the pulmonary arteries and subsequently varies. An inflammatory leukogram is possible3. Hyperglobulinaemia due to antigenic stimulation is an inconsistent finding1, 3. Right-sided heart failure or immune-complex glomerulonephritis can lead to hypoalbuminaemia and, very occasionally, nephrotic syndrome1. Because of this, it is possible for urinalysis to reveal proteiunuria1, 3. Haemoglobinaemia and haemoglobinuria are associated with caval syndrome3.

Dirofilariasis. Courtesy of T. Scase

There are several methods for the specific demonstration of Dirofilaria immitis in the animal. Firstly, direct microscopic examination allows rapid identification of microfilariae in a drop of fresh blood, as their movements can vigorously displace the surrounding red blood cells2. Despite being quick, simple and inexpensive, this test is not sufficiently sensitive to provide a definitive diagnosis, particularly when there is a low concentration of microfilariae in the bloodstream. Filtration methods therefore exist to facilitate the microscopic demonstration of microfilariae2, 3. These include the modified Knott's test, which involves haemolysis, centrifugation and staining with methylene blue before direct examination. Tests such as this are more sensitive than merely examining a drop of blood, and the morphology of microfilariae can be clearly seen. However, sensitivity in comparison to other methods is still low and so microfilarial identification tests are often reserved for confirmation of weak positive antigen tests and determination of microfilarial status prior to treatment with a microfilaricide3. Cats frequently lack circulating microfilariae, and so direct microscopic examination is of little use in this species.

Dirofilariasis. Courtesy of T. Scase

Tests exist to detect D. immitis antigens. ELISAs specific for proteins released from the reproductive tract of adult female worms are available for in-house use2. Sensitivity and specificity are excellent, but small worm burdens and the presence of immature female- or male-only infections can give low antigen titres hence false negatives. This is especially common in cats. Specific agglutination and immunochromatography techniques are also available for use in dogs. Any antigen test performed in the first six months of infection may give false negative results as levels of circulating antigen are initially low while female worms mature. In-house tests are also available to detect antibody against Dirofilaria immitis. The presence of antibodies confirms exposure, but does not necessarily provide information about current infection. These tests are therefore most useful for ruling out infection. D. immitis antibody tests have a low specificity2 and so have largely been superceded by tests for antigen.

PCR-based tests are highly sensitive and specific for the diagnosis of immature and adult heartworms, and are especially useful in unconventional (e.g. wildlife) hosts2. At present, these tests are not widely available for the diagnosis of Dirofilaria immitis.

Pathology

On post-mortem examination, Dirofilaria immitis worms are apparent in the pulmonary artery and possibly the right side of the heart. The right side of the heart is found to be enlarged and there is proliferation of the pulmonary arterial myointima. Pulmonary thromboembolism and haemorrhage may be seen. If right-sided congestive heart failure was present in life, hepatomegaly and hepatic congestion will be apparent.

Treatment

Animals with right-sided congestive heart failure require stablisation with diuretics, ACE inhibitors and cage rest before treatment for heartworm disease is implemented. Animals with severe respiratory signs also require stabilisation with oxygen supplementation, anti-inflammatory doses of corticosteroid and anti-thrombotic drugs.

The specific adulticidal treatment for Dirofilaria immitis is melarsomine dihydrochoride, a new generation arsenical compound. Melarsomine is administered intramuscularly into the epaxial muscles, and pressure should be applied during and after needle withdrawal3. A "graded-kill" protocol is recommended: an initial injection is followed one month later with two injections at an interval of 24 hours, given on opposite sides1-4. This spreads the killing effects over two treatments, with an aim to reducing the occurrence of thromboembolism after parasite death. Cage rest and anti-inflammatory doses of corticosteroids in the week following melarsomine treatment can also reduce the likelihood of pulmonary thromboembolism. Antigen testing four months after adulticidal treatment will determine whether it is necessary to repeat the therapy3.

Adulticidal treatment may be declined by the owner, owing to the risk of thromboembolism. Alternatively, it may not be possible to implement adulticidal treatment if the patient is suffering renal or hepatic failure3. In these cases, monthly administration of prophylactic doses of ivermectin is a reasonable treatment option, as it prevents further infection and may kill some adult nematodes2.

Even low grade infections in cats may result in pulmonary thromboembolism with adulticidal treatment. Because of this, symptomatic treatment of sick cats may be followed by surgical or catheter-based extraction of nematodes once the patient is stable3. Stablisation is similar to that for feline asthma, and can include cage rest, oxygen supplementation, bronchodilators (e.g. theophylline), tapering doses of prednisolone, and balanced fluid therapy if indicated3. Heartworms have a much shorter life-span in cats, and spontaneous remission is seen in some cases. Regular monitoring may therefore be the best course of action in clinically well cats.

In caval syndrome, surgery is the treatment of choice. Worms are removed from the right side of the heart and the main pulmonary artery using flexible crocodile or basket-type retrieval forceps2. This procedure is complex and requires general anaesthesia and fluoroscopic imaging, but reduces the risk of thromboembolism following subsequent adulticidal treatment. Symptomatic and supportive therapy to stabilise the patient should be continued for around one month after surgery before adulticidal treatment is administered3.

No drugs are specifically approved for microfilaricidal treatment of Dirofilaria immitis, and successful elimination of adult worms should result 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.

Heartworm prophylaxis should be implemented in all cats and dogs living in or visiting areas in which Dirofilaria immitis is endemic. Ivermectin or milbemycin oxime can be given per os on a monthly basis, and selemectin spot-on is effective when applied each month. If animals have already been exposed to Dirofilaria immitis it may be wise to perform an antigen test before starting treatment. In endemic countries, routine antigen testing six months after the end of the previous heartworm season will detect infections that have slipped through the net, and enable treatment during the mild, early stages of disease3.

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.


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(CABI log in required) 		A review of American heartworm society guidelines for the management of heartworm infections in cats. Guerrero, J.; The North American Veterinary Conference, Gainesville, USA, Small animal and exotics. Proceedings of the North American Veterinary Conference, Orlando, Florida, USA, 16-20 January 2010, 2010, pp 1173-1176, 1 ref.

Epidemiology and prevention of Dirofilaria infections in dogs and cats. Genchi, C.; Guerrero, J.; McCall, J. W.; Venco, L.; Veterinary Parasitology and Parasitic Diseases, Naples, Italy, Mappe Parassitologiche, 2007, 8, pp 145-161, many ref.

Heartworm of dog - its aetiopathogenesis, diagnosis, treatment and prevention. Kundu, P.; Intas Pharmaceuticals Ltd, Ahmedabad, India, Intas Polivet, 2006, 7, 1, pp 106-110, 16 ref.

The utility of echocardiography in the diagnosis of feline heartworm disease: a review of published reports. Defrancesco, T. C.; Atkins, C. E.; Seward, R. L.; Knight, D. H.; American Heartworm Society, Batavia, USA, Recent advances in heartworm disease: Symposium '98, Tampa, Florida, USA, 1-3 May, 1998, 1998, pp 103-106, 20 ref.




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Cardiopulmonary Dirofilariasis
Arthropod-borne Infectious Diseases of the Dog and Cat
Susan E. Shaw, Michael J. Day
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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. Venco, L (2007) Heartworm (Dirofilaria immitis) disease in dogs. Dirofilaria immitis and D. repens in dog and cat and human infections, 117-125.
  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. Ridyard, A (2005) Heartworm and lungworm in dogs and cats in the UK, In Practice, 27(3), 147-153.


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