The nematode Dirofilaria immitis, commonly called heartworm, is an important canine and to a lesser extent feline endoparasite. It is classified as a member of the suborder Spirurida and within that of the family Onchocercidae. The main representative of the genus Dirofilaria is D. immitis, but another closely related Dirofilaria species, Dirofilaria repens, is also known to infect dogs and cats (subcutaneous dirofilariosis).
Dirofilaria immitis and its clinical aspect, heartworm disease, can be found in tropical and temperate regions of the world, with the highest known prevalence in the USA, South America, Japan, Australia and Italy.
In the USA, the spread of the heartworm disease was monitored extensively over the last years. In a matter of 50 years, the disease spread from a well restricted south-eastern coastal area of the United States to the point where it is considered now that heartworm is at least regionally endemic in each of the contiguous 48 states, Hawaii, Puerto Rico, US Virgin Islands, and Guam, as well as in most of the Canadian provinces. Major reasons for this dramatic development have been attributed to the increased transport of dogs from southern areas for hunting and breeding, the movement of dogs belonging to army personnel and to normal citizens and the burgeoning wild canids population, like the Californian coyote. Once a reservoir of microfilaraemic domestic and feral canids is established beyond the reach of veterinary care, eradication becomes much more difficult.
In Europe, heartworm still appears to be more confined, for the most part, to southern European countries like Portugal, Spain, France, Italy, Slovenia, Bulgaria, Romania, Greece and Turkey. But cases have also been reported from Hungary, Slovakia and Czech Republic. Infections in Serbia and Croatia have increased from sporadic to occurring. For European occurrence see also CVBD World Occurrence Map. The largest European endemic area is localized in Northern Italy in the Po lowlands with prevalences in dogs up to 50 or even 80%. As pet travel with their owner increases, there may be an increased risk of spread.
Like all other members of this family of nematodes, the development of Dirofilaria immitis requires both an arthropod and a mammalian host. First, adult female heartworms release microfilariae into the animal's bloodstream. Then, mosquitoes become infected with microfilariae while taking a blood meal from the infected animal. During the next 10 to 14 days, the microfilariae mature to the infective larval stage, a third-stage larva (L3) within the mosquito’s Malpighian tubules.
After that time, the infective larvae make their way into the head and mouthparts of the mosquito and then enter another host – e.g. another dog, cat or other susceptible animal – during mosquito feeding. Seventy days after infection, migration and exsheathment to the adult stage inside the vertebrate host is complete. Approximately 6 months after infection, female adult worms contain mature microfilariae.
This generation of microfilariae cannot mature into adult heartworms without first passing through a mosquito. Patent infections, i.e. infections with detectable microfilariae in the blood, are observed typically 7 to 9 months post infection; when patency is measured using the presence of circulating antigens (glycoproteins from female worms), these moieties may be found in the blood as early as 5 months after infection.
The ubiquitous presence of one or more species of vector-competent mosquitoes makes transmission possible wherever a reservoir of infection and favourable climatic conditions coexist.
A pivotal prerequisite for heartworm transmission to occur is a climate that provides adequate temperature and humidity to support a viable mosquito population, and also sustain sufficient heat to allow maturation of ingested microfilariae to infective L3 within this intermediate host. In mosquitoes under optimal temperatures above 26°C, infective larvae can develop in around 10 days to two weeks. Since development in the mosquito is temperature related, the peak months for heartworm transmission in the Northern Hemisphere are July and August.
After infection with Dirofilaria immitis L3 during mosquito feeding, the larvae grow, develop and migrate in the body over a period of several months to become sexually mature male and female worms. Adult heartworms live primarily in the pulmonary arteries of infected hosts. Seldom they are found in the right cardiac chamber and large adjacent vessels (cranial and caudal vena cava). Ectopic localizations (i.e. brain, eyes and aorta) can rarely occur.
Dirofilaria offspring, so-called microfilariae, can be detected in the peripheral blood (pre-patent period) about six to seven months after the infective larvae entered the dog during the blood meal of an infected mosquito. Male (10-15 cm in length) and female (25-30 cm in length) heartworms appear to possess a life span in dogs that averages up to five to seven years.
Microfilaraemia, the presence of heartworm offspring in the blood of infected dogs, is relatively common. However, not all heartworm infections result in microfilariae circulating in the blood. Infections not showing microfilaraemia are known as occult heartworm infections and may be the result of a number of factors such as single sex heartworm infections, host immune responses affecting the presence of circulating offspring (microfilariae) and most significantly, the administration of heartworm preventives.
Lesions of the endothelial surface of pulmonary arteries are the first step in the pathogenesis of the disease.
Activated neutrophils adhere to the endothelial surface and enter the space between the lining endothelial cells. Furthermore, as linear areas of subendothelium are exposed, platelet adhesion and activation are greatly stimulated. After the endothelial changes, the intima thickens with fluid, leukocytes invade the wall and smooth muscle cells multiply within the tunica media and migrate toward the endovascular surface as response to growth factor release. In the end, villi are present on the internal arterial surface, appearing rough and velvety, and both the lumen and the compliance of the pulmonary arteries are reduced.
Lung disease occurs secondary to vascular changes. Fluid and protein leaking through the vessel walls of affected arteries produce oedema. Spontaneous death of single worms can cause thromboembolism and severe inflammatory reactions. Occlusion by either thromboembolism or villous proliferation results in a hypertensive pulmonary state and, as a consequence, in an increased afterload for the right ventricle which can induce a "cor pulmonale" and congestive heart failure in dogs. The right cardiac ventricle is involved in the disease not before the last stages.
The earliest time point that heartworm antigen and microfilariae can be detected is about 5 and 6.5 months post infection, respectively. Depending on the sensitivity of the particular heartworm antigen test, antigenaemia may precede, but sometimes also lags behind the appearance of microfilariae by a few weeks.
Whether screening a population of asymptomatic dogs or seeking verification of a suspected heartworm infection, antigen testing is the most sensitive diagnostic method. The current generation of heartworm antigen tests identify most "occult" (microfilaria negative) infections, consisting of at least one mature female worm, and are nearly 100% specific. Microfilaria testing is complementary and is recommended meanwhile to be done in tandem with antigen testing. This is especially important if there is a high degree of suspicion or if the heartworm prevention history is unknown. Additionally, in some dogs infected with heartworms, antigen blocking, presumably from antigen–antibody complexes, may lead to false-negative antigen test results. These dogs will be antigen negative and possibly microfilariae positive. Nevertheless, there will be instances where an infected dog is both antigen and microfilaria negative.
ELISA and immunochromatographic test systems are available for detecting circulating heartworm antigen. Each testing format has proved to be clinically useful. Differences in sensitivity exist especially in cases with low worm burdens and/or low antigenaemia. Currently there are no verified tests capable of detecting infections consisting of only adult male worms. False-negative as well as false-positive results can occur. In a case of an unexpected test result, the test should be repeated and if still questionable, independent confirmation by a test laboratory is recommended.
The amount of antigen in the circulation system bears a direct but imprecise relationship to the number of mature female heartworms. A graded test reaction can be recognized by ELISA test systems, but quantitative results are not displayed by immunochromatographic tests. Quantitative analysis of antigen results is highly speculative and requires correlation with other relevant information.
If the validity of a weakly positive result is in doubt, verification may be achieved by repeating the test and if still ambiguous, by independent confirmation by some other means, such as a second antigen test format, concentration tests for microfilariae, or ultrasonographic visualization of worms. Upon request, most test manufacturers will analyze ambiguous samples in their own laboratories. It is currently recommended to confirm all positive antigen tests prior to the administration of any therapy.
False-negative test results occur most commonly when infections are light, female worms are still immature, only male worms are present and/or the test kit instructions have not been followed.
Antigen test results should be interpreted carefully, taking other relevant clinical information into consideration. However, in general, it is better to trust rather than reject positive antigen test results, and a negative antigen test results does not verify an animal to be free of heartworm infection; it simply indicates that no antigen could be detected by that particular testing methodology. As such, a negative test result should be interpreted more accurately as no antigen detected (NAD) rather than “negative”.
Most microfilaraemic dogs can be detected by microscopical examination of fresh blood for cell movement created by the motility of the microfilariae. A stationary rather than a migratory pattern of movement is indicative of a Dirofilaria species. Movement beneath the buffy coat in a microhaematocrit tube also may be visible microscopically. However, these are insensitive methods for examining blood in which low numbers of microfilariae (50-100/ml) are present. Therefore, it should not be assumed that no microfilariae are present until at least 1.0 ml of blood has been examined using a concentration technique (modified Knott test or filtration test). The modified Knott test is the preferred method for observing morphology and measuring microfilarial body dimensions to differentiate Dirofilaria immitis from non-pathogenic filarial species such as Acanthocheilonema (formerly Dipetalonema) reconditum. Although screening may be based entirely on antigen testing, antigen-positive dogs should also be tested for microfilariae, because a microfilaraemia validates the serologic results and identifies the patient as a reservoir of infection.
For the modified Knott test in short 1 ml EDTA blood plus 9 ml 2% formalin are mixed and centrifuged. The supernatant is discarded. To the remaining sample methylene blue (0.1%) or methylene green (0.2%) is added and the sediment examined microscopically for microfilariae (see table on details).
Details on the differential diagnosis of microfilariae in the blood of dogs (after Deplazes, 2006)
|Criteria||Dirofilaria immitis||Diroflaria repens||Acanthocheilonema reconditum||Dipetalonema dracunculoides*|
|Approx. length (µm) in stained preparation||205-2831||260-3081||213-2402||246-2583|
|Posterior end||straight||hook-shaped bent||hook-shaped bent (30-40%)||straight|
|Evidence of acid phosphatase5||at excretion and anal porus||at anal porus||diffusely distributed||one spot each on the inner body and the anal porus; circle around excretion porus6|
1Bucklar et al. (1998); 2Whiteley (1988); 3Olmeda-Garcia and Rodriguez-Rodriguez (1994); 4Ducos de Lahitte (1990); 5method: Chalifoux and Hunt (1971); 6Ortega-Mora et al. (1989)
*syn. Acanthocheilonema dracunculoides
Radiography provides the most objective method of assessing the severity of heartworm cardiopulmonary disease. There are few radiographic changes with mild infection. Typical signs of heartworm vascular disease are enlarged, tortuous and often truncated peripheral intralobar and interlobar branches of the pulmonary arteries, particularly in the diaphragmatic lobes. These findings are accompanied by variable degrees of pulmonary parenchymal disease. As the severity of infection and chronicity of disease progress, the pulmonary arterial signs are seen in successively larger branches, and in the worst cases, eventually the right heart also enlarges.
The body wall of adult heartworms is highly echogenic and produces distinctive, short parallel-sided images with the appearance of “equal signs” where the imaging plane cuts across loops of the parasite. Echocardiography can provide definitive evidence of heartworm infection, as well as an assessment of cardiac anatomic and functional consequences of the disease, but is not efficient of making a diagnosis, particularly in lightly infected dogs, since the worms often are limited to the peripheral branches of the pulmonary arteries beyond the echographic field of view. In dogs with haemoglobinuria, visualization of heartworms in the orifice of the tricuspid valve provides conclusive confirmation of the caval syndrome.
Clinical presentation of heartworm infection depends on whether the patient is a dog or a cat and, particular in dogs, the duration of disease and the size and position of the worm burden. The clinical signs can be roughly grouped according to severity into categories of mild, moderate and severe. Not all dogs will necessarily show all signs indicated for the respective category or will exhibit mixed signs. Small dogs, with smaller hearts and blood vessels will tend to show more severe signs with a smaller worm burden than larger breeds.
Mild or sub-clinical stage:
- normal condition of the dog
- asymptomatic or cough
- few worms tolerated without obvious clinical signs
- fair or good condition of the dog
- a degree of exercise intolerance
- occasional coughing during exercise
- abnormal lung sounds
- eventually some pallor indicative of anemia
- possible loss of weight and condition
- intolerance of exercise
- regular coughing, dyspnoea
- increased respiratory rate at rest
- abnormal heart and lung sounds
- enlarged liver
- eventually pale with severe anaemia (PCV < 20%)
The clinical evolution of heartworm disease in dogs is usually chronic. Most infected dogs do not show any symptoms of the disease for a long time, depending on the worm burden, individual reactivity and exercise. Signs of the disease develop gradually and may begin with a chronic cough, maybe followed by dyspnoea, from moderate to severe, weakness, and sometimes faint after exercise or excitement. Later, when right cardiac congestive heart failure is developing, swelling of the abdomen and sometimes the legs, anorexia, weight loss and dehydration are usually noted. At this stage, cardiac murmur due to tricuspid valve insufficiency and abnormal cardiac rhythm due to atrial fibrillation are common findings. Sudden death rarely occurs and usually happens following respiratory distress and cachexia.
Caval syndrome (Vena cava syndrome)
After severe spontaneous thromboembolism following the natural death of many heartworms, dogs may show acute life-threatening dyspnoea and haemoptysis. In addition, even living worms can move out of the pulmonary arteries into the right ventricle and atrium, and rarely into the vena cava, due to pulmonary hypertension and sudden fall in right cardiac output. This caval syndrome is commonly noted in small sized dogs. The worms may move backwards and forwards through the tricuspid valve causing valvular incompetence. Fatal outcome is usual. The following signs may be observed:
- anorexia, severe weakness and lethargy, dyspnoea
- red urine, anemia, pale mucus membranes
- heart failure
- right-sided systolic murmur
- jugular pulse and weak femoral pulse
- liver and kidney dysfunction
The filarial species of the carnivores are zoonotic pathogens. Occasionally D. immitis is transmitted via mosquitoes to humans. In some individuals, worm migration and development occurs, with or without clinical signs. The lungs are the most common location for worm settlement (pulmonal dirofilariosis). There they can cause a "coin lesion" seen on radiography and often being mistaken for a tumor. This may be asymptomatic or may be associated with symptoms including coughing or chest pain. Aberrant migration may also occur.
Treatment & Prevention
Chemotherapy is indicated in asymptomatic as well as symptomatic cases. Treatment against macrofilariae (adult filariae) and microfilariae has to be differentiated. In symptomatic cases supportive treatment is additionally necessary.
The trivalent arsenical melarsamine dihydrochloride is the drug of choice in the therapy against macrofilariae. It is potential against adult and fifth stages of Dirofilaria immitis, but does not possess any activity against microfilariae. It is better tolerated than formerly used drugs, but still has a low drug security index. After adulticidal therapy thromboembolic complications regularly occur, especially in high worm burdens.
After the elimination of adult female worms microfilariae may persist for a long time. Therefore after macrofilaricidal therapy, 5 to 6 weeks later a therapy against microfilariae should be added. The most commonly used heartworm chemotherapeutics are macrocyclic lactones. These drugs have exceptionally high therapeutic/toxic ratios, and possess anthelmintic activity against microfilariae, 3rd and 4th stage larvae, and in some instances of continuous use, juvenile and adult heartworms.
An additional complication after microfilarial therapy is an anaphylactic reaction against liberated microfilarial antigens. The risk is especially high in small dog breeds with high microfilarial density (>10,000/ml). Measurement of microfilarial density and a fractionated treatment over several days may help to prevent those anaphylactic reactions.
The filaricidal effect of oral and topical formulations on precardiac larvae can be achieved by brief pulsing at very low doses or continuous release of small amounts over long periods, which makes these safe drugs highly effective at the prescribed doses and intervals of administration. All orally and topically administered macrocyclic lactone preventive products are labelled for a 30-day dosing interval. Efficacy against late 4th stage larvae declines. As the worms age, they require progressively longer-term administration to achieve a high level of protection.
Caval syndrome (Vena cava syndrome)
Immediate surgical extraction of the worms occluding the vena cava and/or the right atrium is the treatment in the ‘Vena cava syndrome’. Worms are extracted by way of right jugular venotomy using flexible alligator forceps. After a recovery period of two weeks and thromboembolic prophylaxis, regular treatment with adulticidal drugs may be initiated.
Canine heartworm infection is preventable, despite the inherent susceptibility of dogs. Since most dogs living in heartworm endemic areas are at risk, chemoprophylaxis is a priority.
Even though continuous, year-round transmission may not occur throughout the country, year-round use of broad-spectrum chemoprophylaxis products with endoparasitic and/or ectoparasitic activity during this extended period should enhance compliance and may assist in preventing pathogenic and/or zoonotic parasitic infections. Heartworm preventives usually belong to the macrocyclic lactone class of drugs. When given according to label instructions, they are highly effective. Orally and topically administered macrocyclic lactone preventive products are usually labelled for a 30-day dosing interval. A continuous, year-round administration of heartworm preventive is a partial safeguard in the event of inadvertent delay or omission of regularly scheduled doses.
The risk of infection can be also minimised by applying topical drugs which repel and kill the transmitting mosquitoes. Especially for regions, which harbour not only mosquitoes but also sand flies and ticks, it may be suitable to use a broad-spectrum ectoparasiticide. A macrocyclic lactone preventive, concurrent with the use of a topical mosquito repellent-ectoparasiticide, may provide more complete protection from heartworms. Additionally travel of dogs from non-endemic areas into D. immitis endemic regions should be carefully planned or even prevented. Furthermore dogs in endemic areas should be kept inside during the main diurnal vector activity.
Situation in Cats
Significant differences exist between feline heartworm disease and its classical canine counterpart. Although cats are susceptible hosts, they are more resistant to infection with adult Dirofilaria immitis than are dogs. Most heartworm infections in cats are comparatively light and consist of less than six adult worms. Much heavier infections may occur, but usually only one or two worms are present. But because of the relatively small body size of cats, infection with only a few worms is still considered to be heavy in terms of parasite biomass.
Cats possess a greater tendency to exhibit only transient clinical signs or die without confirmation. Circulating microfilariae are seldom found in infected cats. Furthermore it appears that feline infections become occult due to host immune-mediated clearance of the microfilariae and perhaps a reversible suppression of microfilariae production.
The clinical importance of heartworms is amplified in cats because even a small number of heartworms are potentially life-threatening. Although live adult worms in the pulmonary arteries cause a local arteritis, some cats never manifest clinical signs. When signs are evident, they usually develop during two stages of the disease: 1) arrival of heartworms in the pulmonary vasculature and 2) death of adult heartworms. The first stage occurs approximately 3 to 4 months post infection. These early signs are due to an acute vascular and parenchymal inflammatory response to the newly arriving worms and the subsequent death of most of these same worms. This initial phase is often misdiagnosed as asthma or allergic bronchitis, but in actuality is part of a syndrome known as heartworm-associated respiratory disease (HARD). Clinical signs associated with this acute phase subside as the worms mature, but demonstrable histopathologic lesions are evident even in those cats that clear the infection. Once the pulmonary infection is established, evidence suggests that live heartworms are able to suppress immune function. This allows many cats to tolerate their infection without apparent ill effects — until the mature worms begin to die, which initiates the second stage of disease expression. The degenerating parasites result in pulmonary inflammation and thromboembolism, which often leads to fatal acute lung injury. Caval syndrome occurs rarely in cats because infections are usually light; however, even one or two worms may cause tricuspid regurgitation and resultant heart murmur.
Clinical signs associated with feline heartworm disease may be only a vague malaise or can comprise predominantly respiratory, gastrointestinal (e.g., emesis), or occasionally neurologic manifestations, chronically or acutely. Signs of chronic respiratory disease, such as persistent tachypnoea, intermittent coughing, and increased respiratory effort are most common.
Heartworm infection in cats is a more elusive diagnosis than in dogs and can be easily overlooked. Establishing a definitive antemortem diagnosis frequently entails application of multiple diagnostic tests, some of which may need to be repeated. Of these, heartworm serology, thoracic radiography, and echocardiography are the most useful methods of clinical confirmation. Nevertheless due to the fact that cats are seldom microfilaraemic and often possess only male worms or symptomatic immature infections, effectiveness of diagnostic tests differ compared with the situation in dogs. For further details see also the Current Feline Guidelines of the American Heartworm Society (AHS).
Regarding treatment, if a cat displays no overt clinical signs despite radiographic evidence of pulmonary vascular/interstitial lung disease consistent with heartworm disease, it may be prudent to allow time for a spontaneous cure to occur. The course of infection can be monitored at 6- to 12-month intervals by repeated antibody and antigen testing and thoracic radiography. In acutely ill cats, stabilization with supportive therapy is essential, whereas adulticide (melarsomine dihydrochloride) use is not recommended. Ivermectin application has been reported to reduce worm burdens, and surgical removal might also be an option. Finally, monthly heartworm preventives are a safe and effective option for cats in areas where heartworm infection is considered endemic in dogs. Again, for more details see also the Current Feline Guidelines of the American Heartworm Society (AHS).
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