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Heartworm disease in the dog

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Category: Schede
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  • Disciplina: Parassitologia
  • Specie: Cane

Heartworm disease (cardiopulmonary filariasis) is a serious parasitic disease caused by a nematode, Dirofilaria immitis (Fig. 1), whose adult stage localises in the pulmonary arterial system, in the chambers of the right side of the heart and in the large vessels draining into them (the cranial and caudal venae cavae). The natural host of D. immitis is the dog, but more than 30 wild and domestic species can by infested, including the cat.

 

SPREAD

The life cycle of the parasite requires an intermediate host (various species of mosquitoes can transmit the infestation, including Aedesalbopictus, the so-called "tiger mosquito", which differs from other species in that it takes a blood meal during the daytime). The widespread presence of the intermediate host means that the disease is now endemic in many areas throughout the world. The fact that the number of owned dogs that receive prophylaxis in endemic areas is very high should not lead us to believe that the problem of heartworm disease is now resolved and under control. Although systematic use of chemoprophylaxis has effectively reduced the number of dogs infected, the prevalence of this parasitic infection is still very high in animals in the community and among those which undergo erratic prophylaxis or prophylaxis based on products not registered for dogs. Indeed, it has recently been seen that the epidemic areas are spreading both northwards and southwards. It is also erroneous to think that the mere reduction of the reservoir can ensure a lower risk of infestation. The abundance of the vector and a high "force of infection" (i.e. the probability that a susceptible host acquires the infestation within a year) mean that the risk of infestation is still considerable.

 

CLINICAL ASPECTS

In dogs, the parasitic infestation typically has a chronic course during which there are only occasionally acute exacerbations (vena cava syndrome, spontaneous thromboembolism). Cough is usually the first symptom seen, in association with inflammatory lesions of the lung parenchyma. The possible subsequent onset of severe, progressive pulmonary hypertension is certainly the central phase of the pathogenesis and is caused by an increase in pulmonary arterial resistance. The adult parasites cause chronic progressive damage that results in both a reduction of the vascular lumen (proliferative thromboembolic damage) and structural alterations of the vessel wall (reduction of vascular compliance) (Fig. 2).

Pulmonary hypertension is, therefore, the natural consequence of the progressive increaseof pulmonary resistances and is manifested clinically as syncopal episodes, particularly during physical exercise. This puts the right ventricle (which, given its anatomical and functional characteristics, is able to tolerate overloads of blood volume well but not significant increases in afterload, i.e. pressure overload) in a situation of considerable difficulty and, over the mid- to long-term, leads to ventricular dilatation with reduced inotropism and severe alterations of the valves (in particular the tricuspid valve). From a clinical point of view this can be reflected by episodes of syncope, initially during exerciseand subsequently at rest or in particular situations (e.g. after a persistent cough). In the dog congestive right heart failure, with its classic signs (hepato-splenomegaly, ascites, hydrothorax, oedema of the limbs), should be considered as the last, natural and, in most cases, irreversible step in the evolution of the disease.

 

DIAGNOSIS

The diagnosis of heartworm disease is reached from the results of some diagnostic procedures and tests. It is important to remember that about 5 months passes between the moment of transmission from the intermediate host and the appearance of detectable antigens in the definitive host. The same is true for the appearance of microfilariae in the blood (prepatency period, which is estimated to be about 6.5 months). For this reason diagnostic tests should not be performed earlier than 7 months after the end of the period of risk of transmission of the parasite.

The antigen test is considered the gold standard for the canine species in that it combines very high sensitivity and specificity. It detects antigens produced by the adult, female parasite and provides a certain diagnosis of the disease. False negative results are possible in cases of mild infestations or infections caused by male adults only (these latter can be diagnosed only at post-mortem examination), but are uncommon and of little clinical relevance. The clinical examination, which must always be performed before the diagnostic investigations, will be very useful in interpreting the results.

The evaluation of microfilaraemia (Knott’s test) (Fig. 3) is a rapid and easily performed procedure that enables the detection of microfilariae in the blood circulation. It is highly specific, because finding the immature parasite in the blood is definite proof of infestation, and has a good sensitivity since it is very common to find microfilariae in the blood of dogs. However, it is worth remembering that cases of occult heartworm are not uncommon: in these cases the parasite is present in the body but the microfilariae are not detectable. In occult cases the antigen test gives a positive result, while Knott’s test is negative. Evaluation of microfilaraemia alone may, therefore, be misleading and result in an erroneous diagnosis in the case that the test is negative. A negative antigen test is not, in any case, infrequent in animals infested with heartworms. For this reason both of the above mentioned tests should be performed to increase the diagnostic sensitivity.

As regards parasite load and the damage to the heart and lungs caused by the parasites, ancillary diagnostic techniques are needed to stage the disease.

In particular, chest X-rays provide important information on the lesions in both the parenchyma and vessels of the lungs, but not about the parasite load, for which echocardiography is more reliable(Figs. 4a and 4 b).

The adult parasites can only be identified by ultrasound studies if they are in sites that can be investigated by ultrasonography. Such sites include the right heart chambers, the distal parts of the veins emptying into these chambers (cranial and caudal venae cavae), the common branch of the pulmonary arteries, a long segment of the right caudal lobar pulmonary artery and a short part of the left one, because of the interference caused by the air-filled lung parenchyma. It is essential to investigate all these sites, even though the microfilariae most frequently localise in the common branch and the right lobar branch. Since these nematodes have a hyperechoic cuticle, they are easily seen by ultrasonography as hyperechoic, double-walled images floating freely in the vessel lumen or in the right heart chambers (Fig. 5).

 

Echocardiography

 

 

 

 

 

 

Echocardiographic visualisation of the adult worms is usually associated with particularly high parasite loads. Echocardiography also enables a detailed assessment of any morphological or functional changes to the heart and large vessels caused by the parasite(Figs. 6a, 6b and 6c).

In dogs with haemoglobinuria, the visualisation of parasites at the tricuspid valve enables the diagnosis of vena cava syndrome to be made.

 

TREATMENT PROTOCOL

After having made the diagnosis of heartworm, the choice of treatment is based on a systematic and rational evaluation of the patient and requires good knowledge of the pathophysiological mechanisms of the disease and of the treatments available. The aims of the treatment selected should be to achieve the best possible condition of the patient and the longest duration of life together with healing from the parasitic infestation, providing that evaluation of the risk/benefit ratio does not indicate that this last aim should not be pursued.

It is, therefore, essential to establish the entity of the disease by collecting a minimal set of data from the history, clinical examination, chest X-rays, semi-quantitative serological studies to evaluate circulating antigens and/or echocardiography. This information can be used to verify that the clinical picture is due to the parasitosis and not to other concomitant disorders that could mimic the signs (e.g. mitral regurgitation, tracheal collapse and chronic bronchial disease) and to establish the best treatment.

A rational approach to the management of heartworm in the dog starts from the diagnosis of the parasitic infestation, reaching targeted treatment through various essential steps that should not be overlooked or underestimated.

Evaluation of thromboembolic risk

When choosing the targeted treatment on the basis of the clinical investigations carried out, it is important to consider the risk of thromboembolism due to the macrofilaricide treatment selected. Two factors determine the level of this risk:

  • the parasite load
  • pulmonary vascular disease

The parasite load can be evaluated by performing semi-quantitative tests to identify the circulating somatic antigen of D. immitis and by two-dimensional echocardiography.

The severity of the changes in the pulmonary arterial circulation is better evaluated through the interpretation of good quality chest X-rays, Doppler echocardiography and, in subjects without other heart disorders, levels of pro-B-natriuretic peptide in the blood.

It is important to appreciate that radiographic evaluation of the patient cannot alone provide an accurate estimation of the parasite load. In fact, heartworm is a disease in which the parasite load accumulates and gradually increases until reaching a maximum level in the patient’s middle age and then decreases progressively as the animal becomes elderly because of spontaneous death of some of the adult worms. The vascular changes, caused mainly by phenomena of spontaneous thromboembolism due to the natural death of the parasites, are manifested and gradually worsen with increasing age. For this reason, in hyper-endemic areas relatively young infested subjects may have very high parasite loads but still have fairly normal X-ray pictures, leading to a mistaken evaluation of a low thromboembolic risk from adulticide therapy.

Classification of thromboembolic risk following causal treatment

Based on the findings of the clinical and instrumental investigations aimed at determining the parasite load and existence of any changes in the pulmonary vasculature, two classes of thromboembolic risk can be identified.

The “low thromboembolic risk” class

Low parasite load and lack of pulmonary vascular changes. Subjects in this class must have all the following characteristics:

  • No symptoms;
  • No detectable change on chest X-ray studies;
  • Semi-quantitative antigen test for the detection of circulating antigens weakly positive or negative with microfilaraemia present;
  • No echocardiographically demonstrable adult worms in the proximal parts of the pulmonary artery circulation;
  • No concomitant severe pathology;
  • Owners able to carry out all the suggested therapeutic instructions.

The “high thromboembolic risk” class

High parasite load and/or presence of pulmonary vascular changes. The subjects in this class have at least two of the following characteristics:

  • Symptoms;
  • Detectable change on chest X-ray studies (pulmonary vascular disease);
  • Semi-quantitative antigen test for the detection of circulating antigens moderately to strongly positive;
  • Echocardiographically demonstrable adult worms in the proximal parts of the pulmonary artery circulation;
  • Concomitant severe pathology;
  • Owners not able to carry out all the suggested therapeutic instructions.

Factors contributing to reducing the risk of thromboembolism following causal therapy

Rest
Rest is the most important factor for reducing the degree of thromboembolism. Specific research has demonstrated that following targeted treatment of adult worms, even a few minutes’ walk on a leash can significantly increase the severity of the pulmonary changes.

Anticoagulants
Calcium heparin is the only anticoagulant that has been shown to be able to lower the incidence and reduce the severity of thromboembolic reactions. The recommended dose is 50-100 IU/kg subcutaneously every 12 hours starting 1 week before the treatment of the adult parasites and continuing for the subsequent 40 days. It should be noted that acetylsalicylic acid has been found to be ineffective in this context and is not, therefore, recommended. Although specific studies have not been published on the use of low molecular weight heparins (at the same dose) for the prevention of thromboembolism in animals with heartworm, such forms of heparin are generally more effective than calcium heparin at preventing thromboembolic phenomena  (because of partial inhibition of factor X). Calcium heparin, in contrast, has been shown to be more effective once such phenomena are already underway. There are, therefore, theoretical presuppositions for the use of low molecular weight heparins in animals with heartworm.

Corticosteroids
Prednisolone at a dose of 0.5 mg/kg administered orally on alternate days in the 2 weeks following adulticide treatment with melarsomine has reduced the severity of pulmonary changes due to such treatment in experimentally infested animals. Data are lacking on its use in the field.

Doxycycline
Experimental studies seem to suggest that the administration of oral doxycycline at a dose of 10 mg/kg for the 30 days preceding the first administration of melarsomine, by eliminating 90% of the endosymbionts of the macrofilariae (Wolbachia spp.), can reduce the subsequent risk of thromboembolism caused by the death of the parasites. However, this has not yet been confirmed in the field.

 

RECOMMENDED TREATMENT

“Low thromboembolic risk” class

  • Melarsomine dihydrochloride 2.5 mg/kg once (partial treatment); then, after 50 days, full treatment with melarsomine at a dose of 2.5 mg/kg given twice at an interval of 24 hours together with mild restriction of physical activity for 4 -5 weeks after each dose of melarsomine.

“High thromboembolic risk” class

In all cases, symptomatic treatment until the specific symptoms have disappeared or become less intense. Depending on the particular characteristics of each case, different therapeutic options are available:

  • Melarsomine dihydrochloride 2.5 mg/kg once (partial treatment); then, after 50-90 days, complete treatment with melarsomine at a dose of 2.5 mg/kg given twice at an interval of 24 hours together with a drastic restriction of physical activity and administration of an anticoagulant (heparin) started 1 week before the treatment and continued for up to 40 days after its completion.
  • In subjects with a high parasite load detected by ultrasound:
    • Surgical treatment (transvenous removal of the adult heartworms using flexible alligator forceps) followed, after 4 months, by the antigen test and, in the case of positivity, by treatment with melarsomine dihydrochloride using the regimen for the “low thromboembolic risk” class of animals.
  • In subjects in which the risk of thromboembolism is considered unacceptable in comparison with the advantages to be gained from a parasitological cure (elderly and asymptomatic animals):
    • No causal treatment. Establishment of appropriate prophylaxis with a compound carefully chosen on the basis of the characteristics of the microfilariae and/or macrofilariae (ivermectin, moxidectin, milbemycin oxime, selamectin).
  • Subjects with vena cava syndrome:
    • Surgical treatment (transvenous removal of the adult heartworms using flexible alligator forceps) followed, after 4 months, by the antigen test and, in the case of positivity, by treatment with melarsomine dihydrochloride using the regimen for the “low thromboembolic risk” class of animals.

Surgical therapy (transvenous removal of the adult heartworms using flexible alligator forceps)

Transvenous surgical removal of the adult worms has been shown to give a better prognosis compared to medical treatment in subjects with a high parasite load. It avoids the risk of thromboembolism and has a perioperative mortality risk close to 0% in subjects with chronic infestation and macrofilariae in the pulmonary arteries; although the perioperative risk rises to 30% in subjects with vena cava syndrome or dirofilarial haemoglobinuria, surgery is the only applicable therapy(Figs. 7, 8 and 9).

 

Microfilaricide therapy

Microfilaricide therapy is the last stage of the causal treatment aimed at eliminating the parasites and should only be undertaken once the adult stages have been eliminated. The same active principles are used as those for prophylaxis against the infestation, but taking into due account the different characteristics and the different administration regimens.

Alternative treatments

It is important to appreciate that the following treatments have been tested only in the laboratory and evidence confirming their efficacy and safety in the field is lacking. For this reason the veterinarian must take full responsibility for their use and must give correct information to the patient’s owner.

Ivermectin: long-term administration

Long-term treatment with ivermectin consists of an oral dose of 6 mg/kg once a month for 24-36 months with mild restriction of physical activity and periodic X-ray controls at least every 6 months. It should be noted that this type of treatment does not eliminate thromboembolic phenomena but dilutes them over a much longer time, obliging rest for prolonged periods (2 or 3 years) and the possibility of developing chronic pulmonary hypertension remains. It is, therefore, a treatment that should not be used in subjects with already instrumentally documented signs or alterations to the pulmonary arterial circulation, in subjects with high parasite loads and is subjects that are very active. The sphere of use of this therapy is, therefore, very limited.

Ivermectin/doxycycline: long-term administration

In cases in which adulticide treatment with melarsomine or surgical removal with flexible alligator forceps cannot be used, it has been demonstrated in the laboratory that the administration of ivermectin (once or twice a month at a prophylactic dose) and doxycycline (10 mg/kg/day for 30 days) causes an overall reduction of 78% in parasite load over the arc of 36 weeks. It should be emphasised that the microfilariae in subjects treated with doxycycline are not able to evolve into parasites when introduced into other subjects, thus reducing the risk of selection of strains of macrofilariae resistant to the macrocyclic macrolides used as prophylactic drugs; in contrast, this is a relevant problem in subjects treated for long periods with only ivermectin.

 

PROPHYLAXIS

Given the risks of the pathology and its treatment, whether medical or surgical, preventive measures to protect the patients from infestation are strongly recommended. Prophylactic treatment consists of macrocyclic lactones: monthly doses of oral ivermectin, moxidectin, or milbemycin oxime, or spot on selamectin or moxidectin, or moxidectin in a long-acting formulation. Chemoprophylaxis remains the first choice to guarantee protection from an extremely severe disease, in which the treatment is complex with potentially fatal complications. The so-called repellent or anti-feeding (permethrin) products do not provide sufficient protection.

 

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