Clarke E. Atkins, DVM, DACVIM
While most dogs and cats infected with heartworms (HWI) are asymptomatic, many have lesions of the pulmonary arterial tree, the lungs, and secondarily the heart. Serious and sometimes fulminant complications to HWI include pulmonary thromboembolism (PTE), caval syndrome (CS), glomerulonephritis, anemia, thrombocytopenia, disseminated intravascular coagulation (DIC), aberrant heartworm migration, and reactions to adulticidal and microfilaricidal therapies. As CS is discussed elsewhere in this congress, it is not covered here. Likewise DIC is beyond the scope of this discussion and space constraints prevent discussion of some of the other less important complications.
Complications and Specific Syndromes
Allergic Pneumonitis. Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course.9,16 In fact, the pathogenesis probably involves immunological reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of heartworm disease, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles, in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar pattern, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples.
Corticosteroid therapy (prednisone or prednisolone at 1-2 mg/kg per day), results in rapid attenuation of clinical signs with radiographic clearing in less than a week. The dosage can then be stopped in 3-5 days, as described above, if clinical signs subside. While microfilaricidal therapy is typically not indicated, as infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be employed after clinical improvement.
Microfilaricidal therapy--adverse reactions. Despite the fact that no agent is FDA-approved for the elimination of microfilaria, microfilaricidal therapy is traditionally instituted 4-6 weeks after adulticide administration.16 The macrolides offer a safe and effective alternative to levamisole and dithiazanine. Microfilariae are rapidly cleared with ivermectin at 50 ug/kg (approximately 8 times preventative dose) or milbemycin at 500 mg/kg (preventative dose), although this represents an extra-label use of ivermectin. Adverse reactions, the severity of which is likely related to microfilarial numbers, were observed in 6% of 126 dogs receiving ivermectin at the microfilaricidal dose.65 Signs included shock, depression, hypothermia, and vomiting. With fluid and corticosteroid (dexamethasone at 2-4 mg/kg IV) therapy, all dogs recovered within 12 hours. One fatality, however, was observed 4 days after microfilaricidal therapy. Similar findings and frequency have been reported with milbemycin at the preventative dosage.38 Dogs so treated should be hospitalized and carefully observed for the day. Dogs <16 kg, harboring >10,000 microfilaria per ml blood are more apt to suffer adverse reactions.61 Benadryl (2 mg/kg IM) and dexamethasone (0.25 mg/kg IV) can be administered prophylactically to prevent adverse reactions to microfilaricidal doses of macrolides.
A slower microfilarial kill rate can also be achieved with ivermectin, moxidectin, and selamectin at preventative doses.23,38,39,66 Using either the rapid or slow kill approach rids the patient of microfilariae and sterilizes the female heartworm.
The American Heartworm Society recommends that macrolide therapy, at preventative doses, be instituted 3-4 weeks after adulticidal therapy.25 Accelerated microfilarial destruction can be achieved using recommended dosages of milbemycin or by reducing the dosing interval for the other topical or oral formulations to every 2 weeks. Filter or modified Knott tests are rechecked in 5 months when using a "slow-kill" or after 2-3 macrolide doses, when using a accelerated dosage.25 This interval for testing can be reduced if milbemycin or high-dose ivermectin (50 mcg/kg) is chosen.
This author chooses an alternative approach, beginning the administration of a macrolide preventative at the time of diagnosis, often days to weeks prior to adulticidal therapy. With the "slow-kill" microfilaricides (ivermectin, moxidectin, or selamectin at preventative dosages), there is little chance of an adverse reaction, but the owner is warned of the possibility, and advised to administer the medication on a day when he/she will be at home. If milbemycin is used, it is administered in the hospital and/or preceded by administration of dexamethasone and benadryl, as described above under adulticidal therapy.
Pulmonary embolization. Spontaneous or post-adulticidal thromboembolization (PTE) with dead and dying worms, the most important heartworm complication, may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7-10 days after adulticidal therapy-often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination.
Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes. The degree of worsening, as compared to pre-treatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is typically most severe in the caudal lobes and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leucocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.
Medical management of thromboembolic lung disease is largely empirical and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50-100 ml/kg), and prednisone (1 mg/kg/day for 3-7 days) are indicated in the most severe cases.14,16,68 Some advocate careful fluid therapy (see recommendations for caval syndrome), measuring central venous pressure to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration.68 The use of heparin (75 IU/kg subcutaneously TID until platelet count has normalized [5-7 days]) and aspirin (5-7 mg/kg/day) has been advocated by some30 but remains controverial.4
Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem).69,70 If vasodilatory therapy is employed, one must monitor blood pressure as hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days' treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.
Clearly, it is better to prevent PTE than to treat it. This is best carried out by strictly curtailing exercise post-adulticide. In addition, the "split-dose" (1 dose, followed by 2, 24-hours apart, in 1-3 months) method of melarsomine administration is advantageous in this regard.
Congestive heart failure. Right heart failure results from increased right ventricular after-load (secondary to chronic pulmonary arterial disease, and thromboemboli with resultant PHT). When severe and chronic, PHT may be complicated by secondary tricuspid regurgitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to HWD will develop heart failure.16 Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.
Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacological and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, as salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal and/or thoracic paracentesis when discomfort is apparent. Furosemide is typically used at 1-4 mg/kg daily, depending on severity and patient response. Additional diuretics, which provide a supplemental effect by utilizing differing parts of the nephron, include spironolactone (12 mg/kg PO BID) and chlorothiazide (2 mg/kg PO QD to QOD). The ACE-inhibitors (enalapril, benazepril, lisinopril, ramipril, etc), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathological cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. There is no evidence that digoxin improves survival. Because of the risk for toxicity and pulmonary vasoconstriction associated with its use, it is not routinely employed by this author in this setting. However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure. Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction may be employed 5 mg/kg/day PO.
The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with HWD and heart failure.69 It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance, right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental-HWD, but without heart failure.70 Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine, as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure, I employ hydralazine at .5-2 mg/kg PO BID, diltiazem at .5-1.5 mg/kg PO TID, or amlodipine at .1-.25 mg/kg/day PO. The risk of hypotension with these therapies must be realized and blood pressure monitored.
Often heart failure follows adulticidal therapy, but if present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4-12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary although slowing the ventricular response to atrial fibrillation with digoxin and/or diltiazem (see chapters on arrhythmias and heart failure) may be necessary in some cases.
References are available upon request.