Canine Heartworm Disease

Matthew W. Miller, DVM, MS, DACVIM (Cardiology)

B efore discussing therapeutic strategies for treatment of dogs with severe heartworm disease i t is necessary to

establish criteria that define severe heartworm disease. Until recently an organized grading scheme has not been available for standardized categorization of dogs with heartworm dis- ease. A clinical clasmflcation scheme has been put forth in an attempt to facilitate communication between clinicians and add some degree of objectivity to the comparison of therapeu- tic interventions. This classification scheme categorizes dogs based on subjective and objective parameters into those with subclinical (mild), moderate, and severe disease. 1 The major parameters used to categorize dogs are listed in Table 1. This article will emphasize management strategies for those dogs considered to have severe heartworm disease.

Although caval syndrome is most certainly a form of severe heartworm disease we will not consider in detail the surgical management of caval syndrome. Many of the concepts outlined in this manuscript, however, are applicable to the therapy of dogs with caval syndrome after surgical reduction of worm burden. Please refer to the manuscript in this issue which deals specifically with this topic. 2,3 The therapeutic strategy for dogs with severe heartworm disease can be divided into several stages: initial stabilization, adulticide therapy, management of thromboembolic disease and evaluation of the efficacy of adulticide therapy. Table 2 provides an outline of the medica- tions commonly employed in the management of dogs with severe heartworm disease.

Initial Stabilization

Eosinophilic Pneumonitis

Eosinophilic pneumonitis is manifested as an intense eosino- philic pulmonary parenchymal infiltrate that develops in response to the presence of adult heartworms (dead or alive) in the pulmonary arteries. Radiographically this appears as dif- fuse bronchointerstitial parenchymal infiltrate (Fig 1). It often causes tachypnea, shortness of breath and cough. Eosinophilic pneumonitis is usually very responsive to corticosteroid therapy with chnical and radiographic improvement commonly seen 2 to 5 days following initiation of therapy. Once clinical response has been noted the dose of corticosteroid should be gradually tapered. Adulticide therapy should be instituted as soon as possible after resolution of clinical signs.

From Texas A & M University, College Station, TX. Address reprint requests to Matthew W. Miller, DVM, MS, DACVIM

(Cardiology), Associate Professor, Texas A & M University, College Station, TX 77483-4474

Copyright © 1998 by W.B. Saunders Company 1071-0949/98/1302-000X$8.00/0

Clinical Techniques in Small Animal Practice, Vol 13, No 2 (May), 1998 pp

Pulmonary Hypertension and Congestive Heart Failure

Signs of congestive heart failure are most commonly associated with severe pulmonary hypertension. Evidence of long stand- ing disease with pulmonary hypertension is readily seen with thoracic radiographs (Fig 2). Myointimal proliferation, villous endarteritis, thromboembolism, reactive pulmonary vasocon- striction secondary to alveolar hypoxia and to a much lesser extent, physical obstruction from the adult worms all play a role in the pathogenesis of pulmonary hypertension. Strict cage rest is the cornerstone of the management of these patients. Numerous studies have documented the dramatic affects of even mild physical activity on pulmonary hemodynamics. 4,5 There is little that can be done to address many of the factors that contribute to elevated pulmonary vascular pressures and ultimately pulmonary hypertension. The inflammatory vascu- lar changes and the physical presence of worms respond only to worm elimination and time. Administration of vasodilating drugs may be associated with some reduction in pulmonary vascular resistance. It is important to remember that the pulmonary vasculature is markedly abnormal in these patients and, therefore, would not be expected to respond normally to vasodilating drugs. 6 Peripheral vascular dilation may be much more dramatic than the degree of pulmonary vascular dilation. This can result in marked reductions in systemic blood pressure with minimal benefit with regards to pulmonary vascular pressure.

Most successful management strategies are directed at im- proving alveolar oxygenation with resultant pulmonary vasodi- lation. 6 Supplemental oxygen admimstration is the most expe- dient way to affect this type of response. Corticosteroid therapy may Improve alveolar oxygenation indirectly by reducing pulmonary inflammation. Administration of bronchodilators (TheoDur [Schering-Plough, Kenilworth, NJ] 10 mg/kg by mouth twice daily) may improve alveolar oxygenauon through elimination of bronchocorlstriction commonly associated with pulmonary inflammation. In dogs with severe arterial changes and pulmonary parenchymal infiltrate, supplemental oxygen therapy may yield dramatic clinical results.

Most dogs with severe pulmonary hypertension have signs attributable either to decreased cardiac output (weakness, exercise intolerance, collapse) or elevated venous pressure and congestion causing ascites with or without concurrent pleural effusion. Aggressive use of diuretics should be avoided if at all possible in these patients. Administration of high-dose diuret- ics typically causes reductions in circulating plasma volume and reductions in cardiac output. If patients have overt signs of respiratory compromise secondary to substantial amounts of pleural or abdominal effusion accumulation physical removal is much more beneficial and associated with minimal complica- tion. Medical management of right-sided congestive heart failure should be directed at augmenting cardiac output by optimizing heart rate augmenting myocardial contractility and

113-118 1 1 3

TABLE 1. Parameters Used to Classify Severity of Heartworm Disease

Parameter Class 1--Subclinical Class 2--Moderate Class 3---Severe

Parasitologlc Diagnosis Negative or "weak" positive result on Positive result on test for HW Ag semlquantitative test for HW Ag Knott test may be positive or negative

If Ag test negative: positive Knott test

History No clinical signs

Physical Examination

Electrocardiography

Thoracic Radiography

Good general condition

Mild to moderate exercise intolerance Occasional cough with exercise

Good/Fair general condition

Normal Normal + / - Evidence of RVH

Normal cardiac silhouette; + / - mildly enlarged pulmonary arteries; + / - mild pulmonary parenchymal infil- trate

Laboratory Data Normal

Moderate enlargement of the nght ven- tricle and main pulmonary artery; moderate enlargement of the caudal pulmonary arteries with evidence of truncation and tortuosity; diffuse perlvascular parenchymal infiltrates

+ / - moderate anemia (PCV 20-30%) Mild to moderate protelnuria common

Prognosis Good Good/Fair

Positive test for circulating HW Ag; Usually highly positive when using a semiquantltative test

Knott test may be positive or negative Marked exercise intolerance, weight

loss Increased respiratory rate at rest, per-

sistent cough Fair to poor general condition; evi-

dence of right heart failure: (ascites, jugular venous distention)

Right ventricular hypertrophy Right axis shift or RBBB Arrhythmias (VPC, A. Fib.) Right ventricular and right atrial

enlargement Enlarged main pulmonary artery;

enlarged, tortuous and truncated lobar pulmonary arteries; diffuse perlvascular pulmonary paren- chymal infiltrates with evidence of PTE

Anemia common (PCV <20%) Significant elevations in hepatic

enzymes and/or BUN and creatlnine; moderate to severe proteinuna common

Guarded

Overlap between categories is common. All abnormalities need not be present to assign a patient to a given category. Classification of older dogs and dogs weighing less than 10 kg should be biased toward the higher class. It should be emphasized that these s~mply represent guidelines for classification. RVH = right ventncular hypertrophy; HW Ag = heartworm antigen; RBBB = right bundle branch block; VPC = ventncular premature complex; A. Fib. = atrial fibrillation; PTE = pulmonary thromboembolism.

TABLE 2. Drugs Commonly Used to Treat Severe Heartworm Disease

Drug/ Intervention Indication Dosage Complications

Prednisolone PTE Eosinophihc pneumonltis

Heparin PTE prevention and therapy of DIC

Melarsomlne HCI Adultlclde

Thiacetarsamide Adultic~de

Supplemental oxygen

Hydralazine*

Diltiazem* Digoxlnl-

PTE, CHF Pulmonary hypertension Pulmonary hypertension, CHF

Pulmonary hypertension, CHF Heart failure, supraventrlcular tachyar-

rhythmlas

Furosemlde:l: CHF

Aspirin§ PTE

1-2 mg/kg divided PO BID taper fol- lowing clinical response

50-100 IU/kg SQ TID or dose sufficient to increase APTT to 1.5 to 2.0 times baseline, start 2 weeks prior to adulti- clde therapy and continue as long as 4 weeks after completion

2.5 mg/kg IM 2 injections 24 hours apart or 1 rejection followed ->30 days later by 2 injections 24 hours apart

2.2 mg/kg IV, 2 injections per day for two consecutive days, 8 hours between injections on the same day, no more than 15 hours between injections 3 and 4

40% FiO2 via nasal insufflatlon or cage

0.5 mg/kg PO initial dose tltrated to 0.5-2.0 mg/kg PO BID

1 0-1.5 mg/kg PO TID 0 22 mg/M 2 PO BID or 0 005-0.01 mg/kg

PO BID

0 5-2 0 mg/kg PO SID-TID

3-10 mg/kg PO SID

Potential to decrease adult worm kill, GI ulceration

Spontaneous hemorrhage

Mild, local celluhtis, excessive salivation PTE following worm death

Severe celluhtls associated with extrava- satlon, acute hepatic and/or renal dys- function; PTE following adult worm death

Long-term exposure to 100% FIO2 may cause lung injury

Systemic hypotension GI anorexia, vomiting Systemic hypotension GI: anorexia, vomiting Cardiac: ventricular arrhythmlas, brad-

yarrhythmlas Hypovolemla, electrolyte and acid/base

abnormalities GI ulceration

*Data regarding the response to vasodllators is sparse and somewhat conflicting; mdw~dual variation is marked and caution should be taken not to cause systemic hypotension. This is especially important when using these drugs in combination with a diuretic.

1-The efficacy of d~goxin in severe heartworm disease ~s controversial, conservative dosing with frequent monltonng of serum dlgox~n levels ~s prudent, if ascites is present an estimate of patient weight without ascltes should be the basis for dosing.

:~High doses of diuretic should be avoided. §The American Heartworm Society does not recommend the routine use of aspirin in dogs with heartworm disease. CHF = congestive heart failure;

2 PTE = pulmonary thromboembollsm; M = body surface area ~n meter squared; DIC = disseminated intravascular coagulation

1 1 4 MATTHEW W. MILLER

Fig 1. Lateral thoracic radiograph from a dog with eosinophilic pneumonitis associated with heartworm disease. Notice the intense and diffuse nature of the bronchointerstitial infiltrate. The pattern of infiltration may take several radiographic forms and may appear nodular as well. The pneumonitis associated with heartworm disease is typically quite steroid responsive.

reducing afterload (reducing the severity of pulmonary hyper- tension). The clinical efficacy of medications including di- goxin, diuretics, Angiotension converting enzyme inhibitors (ACEI) and the vasodllators hydralazine and &ltiazem is variable and poorly described. 6 The effectiveness of conserva- tive management (strict cage confinement, moderate dietary sodium restriction, and supplemental oxygen) should not be underestimated.

Adulticide Therapy

Chemotherapy IMMITICIDE [Merial Limited, Isehn, NJ] (Melarsomine hydro- chloride) has been shown to be more efficacious and safer than sodium thiacetarsamide. 7,8 This is especially true in the setting of severe heartworm disease where a staged reduction in worm burden may be desired. Results of both clinical and laboratory investigations suggest that a split dosing regimen (see Table 2) allows for a staged worm kill. This drug is currently the adulticide of choice for the therapy of heartworm disease in dogs and is an especially welcome alternative to sodium thiacetarsamide in this subset of dogs.

The chemotherapeutic agent sodium thiacetarsamlde is still occasionally used for the elimination of adult heartworms In dogs. The therapeutic regimen recommended by the American Heartworm Society is 2.2 mg/kg IV twice daily for 2 consecu- tive days. Using an increased dose (2.64 mg/kg/injection) is not recommended because a rapid, more complete adult worm kill in patients with severe disease may result in life-threatening

pulmonary embolic disease. Clinical trials suggest that reduc- tion of worm numbers, even without complete elimination of adult worms, frequently results in significant clinical improve- ment. r The goal of initial adulticide therapy should be to reduce the worm burden with improvement in clinical signs.

Much has been written about the affects of corticosteroid therapy on the aduhicidal efficacy of thiacetarsamide. 9 Stud- ies have suggested that steroid therapy prior to adulticide therapy will protect the worms and decrease worm kill. 9 This can be viewed in two ways. First, the data to support this assertion are not nearly as strong as the fervor with which the statement has been perpetuated. Second, if prior corticoster- oid therapy decreases worm adult kill; is that necessarily a bad thing in patients with severe heartworm disease? Would it not be advantageous to kill a portion of the adult worms and obtain some clinical benefit? After administration of adulticide therapy, reinfection could be prevented with the use of appropriate chemoprophylaxis and aduhicide therapy repeated at a later date if necessary. Corticosteroids do not appear to have any adverse effects on the adultictde efficacy of Immiti- cide.7, 8

Recent experimental evidence has confirmed the long held clinical suspicion that the HEARTGARD Plus Chewables [Medal Limited, Iselin, NJ] product containing ivermectin and pyrantel has important adulticidal activity. McCall et al re- ported that administration of HEARTGARD Plus Chewables (administered to provide 6 l~g/kg of ivermectin and 5 mg/kg of pyrantel) for 16 consecutive months provided an incomplete but significant reduction in worm counts relative to untreated

HEARTWORM DISEASE IN DOGS 115

in worm mass may be accomphshed surgmally, chemotherapy to eliminate remaining worms is commonly required and still presents a sigmficant risk (pulmonary thromboembolism) to the patient.

Fig 2. Ventrodorsal thoracic radiograph from a dog with severe heartworm disease and pulmonary hypertension. Notice the dramatic right ventricular enlargement manifested as rounding of the right heart border and the classic "re- versed-D" appearance of the cardiac silhouette. The dramatic dilation and tortuosity of the caudal pulmonary arteries is strong evidence of pulmonary hypertension. Pulmonary hy- pertension can be documented noninvasively with Doppler echocardiography (see manuscript on caval syndrome).

controls and to dogs treated with INTERCEPTOR [Novartis Animal Health] (administered to achieve a dose of 500 pg/kg).I0 Although several people have suggested that this may be the ideal way to manage dogs with severe disease there is currently little evidence to support that claim. Decisions as to whether or not dogs with severe &sease should receive conventional adulticide therapy should take into account the perceived benefits of an exceptionally slow adult worm kill and the potential for progressive pulmonary vascular and parenchy- mal injury. The exact amount of time over which the worms die is unknown.

Surgical Removal

In cases of caval syndrome, surgical removal of worms using an endoscopm basket retrieval device or alligator forceps may result in significant clinical improvement. While the surgical approach to caval syndrome is widely accepted, surgical management of dogs with heavy adult worm burdens without signs typical of caval syndrome is less well estabhshed (Figs 3A and 3B). A recent study demonstrated that percutaneous removal of worms from the pulmonary arteries using a flexible alligator forcep was beneficial in heavily parasitized animals without signs of caval syndrome or congestive heart failure. 11 In this study it should be emphasized that although reductmn

Fig 3. (A) Right parasternal short axis view showing the bifurcation of the pulmonary arteries. The hyperechoic struc- tures within the lumen are adult heartworms. This patient presented for progressive weakness followed by collapse. (B) Necropsy specimen from the patient in figure 3A. Notice the large mass of worms within the opened main pulmonary artery.

1 1 6 MATTHEW W. MILLER

Fig 4, (A) Lateral thoracic radiograph from a dog with heart- worm disease. There are minimal changes typical of heart- worm disease, Since this patient was clinically normal it would be assigned to Class 1 disease status, (B) The same patient 10 days following adulticide therapy. Notice the diffuse interstitial and alveolar pulmonary infiltrate typical of severe embolic disease.

Thromboembolic Disease

Although local celluhtis and acute hepatic or renal toxicity occasionally occur (renal and hepatic toxicity are very uncom- mon with Immiticide), the most serious complication follow- ing aduhicide therapy is thromboembolic disease. Several studies have addressed the topic of thromboembolic &sease yet ideal therapy remains elusive. There is good evidence that the subcutaneous administration of heparin can reduce the sever- lty of thromboembolic disease in dogs with heartworm &sease. In dogs with severe heartworm disease it has been suggested that heparin administration begin as early as 2 weeks prior to aduhicide therapy and continue for 2 to 6 weeks after completion. 12 Dogs presenting with clinical signs of severe

pulmonary embolic disease (shortness of breath, hemoptysis, cyanosis) require aggressive supportive care (Figs 4A and 4B). Strict cage confinement administration of supplemental oxy- gen and cautious fluid therapy are indicated. Heparin therapy should be instituted to combat ongoing pulmonary embolism and for potential beneficial affects on the clinical progression of disseminated intravascular coagulopathy (DIC). The admin- istration of warfarin derivatives or clot lysing agents requires intensive monitoring capabilities and is assocmted with severe potential complications, most notably spontaneous hemor- rhage (Fig 5). The use of diuretics, anubiotics, and bronchodi- lators is somewhat controversial.

Evaluation of Adulticide Therapy

A serologic test for circulating adult heartworm antigen should be performed 5 to 6 months after adulticide therapy. Although some dogs will seroconvert within 12 to 16 weeks of comple- tion of adulticide therapy, a small percentage will not convert for as many as 20 weeks or longer/13,14 Also, if a posiuve test is obtained and the decision to repeat adulticide therapy is made it would be ideal to walt at least 6 months from the time of the first therapy. The adult worms that were not killed during the first adultlclde therapy were most likely immature females, perhaps made more resistant by exposure to corticosteroids (this would only be true if thiacetarsemide was used as the adulticide). If the dog is receiving appropriate chemoprophy- laxis between the ume of initial aduhicide therapy and the decision to repeat therapy, reinfection is extremely unlikely. Clinical improvement associated with reduction of worm mass will make the repeated use of corticosterolds unnecessary. The worms that survived the first regimen of adulticide therapy should be fully mature by the time the decision to repeat aduhlcide therapy is made and therefore the chance of com- plete elimination of adults is maximized by using this regimen. The decision to repeat aduhicide therapy should be made on an individual basis taking into account client expectations in addition to patient parameters including age, concomitant problems, complications with the initial therapy and clinical con&tion. There is an important distinction between heart- worm disease and heartworm infection.

Fig 5. Necropsy specimen from a dog with heartworm dis- ease that died suddenly, A large thrombus is present in the pulmonary artery. Mature thrombi such as this typically do not respond to thrombolytic therapy. Therapeutic measures should include attempts to slow progression of clot expan- sion and promote collateral circulation.

HEARTWORM DISEASE IN DOGS 1 1 7

References

1. Dunavent B, Kelster M, Tanner P, et al. Correlation between heart- worm disease classification, serum antigen concentration, and associ- ated chnlcal pathology parameters. Athens, GA, Rhone Merieux Proc Heartworm Symposium 1995

2. Atklns CE: Pathophyslology of heartworm caval syndrome: Recent advances Proc Heartworm Symp 1989 27-31, 1989

3. Atkins CE, Keene BW, McGuirk SM: Pathophyslology of cardiac dysfunchon m an experimental model of heartworm caval syndrome in the dog: an echocardlographic study. Am J Vet Res 1-19, 1986

4. Dillon AR, Brawner WR, Hanrahan L: Influence of number of D. immit[s and exercise on the seventy of heartworm disease in the dog J Vet Intern Med 10:195-195, 1996

5. Fukam~ N, Hagio M Okano S, et al: Influence of exercise on recovery of dogs following heartworm adultlclde treatment with melarsomlne. The American Heartworm Society: State of the Heartworm Sympo- sium '98.47, 1998

6. Atklns CE, Keene BW, McGuirk SM, et al: Acute effect of hydralazine administration on pulmonary artery hemodynamics in dogs with chronic heartworm disease. Am J Vet Res 55:262-269, 1994

7. Case JL, Tanner PA, Kelster DM, et al: A clinical field trial of melarsomine dlhydrochlorlde (RM340) in dogs with severe (class 3) heartworm d~sease. Proc Heartworm Symposium, 1995.

8. Tanner PA, Kelster DM. Final efficacy results of imm~tlcide used to treat dogs with severe heartworm disease. J Vet Intern Med 8:176, 1994

9. Rawlings CA, Kelth JC, Lewis RE, et al: Aspmn and prednlsolone modification of radiographic changes caused by adultlclde treatment in dogs with heartworm infection. J Am Vet Med Assoc 182:131-136, 1983

10. McCall JW, Ryan WG, Roberts RE, et al: Heartworm adultlcidal activity of monthly prophylactic doses of ivermectin (6 14g/kg) and pyrantel given to dogs. The American Heartworm Society: State of the Heartworm Symposium '98.45, 1998

11. Morlnl S, Venco L, Fagioli P, et al Surgical removal of heartworms vs melarsomine treatment of naturally infected dogs w~th high nsk of thromboembohsm. The American Heartworm Society: State of the Heartworm Symposium '98.49, 1998

12. Vezzoni A, Genchl C: Reduction of post-adulticide thromdoembollc complications with low dose hepann therapy. Proc Heartworm Syrup 73-83, 1989

13. Courtney CH, Zeng Q: Sensitivity and Specificity of Two Heartworm Antigen Tests. Canine Practice 18:20-22, 1993

14. McTier TL, Supakornd~j N, McCall JW, et at" Evaluation of Elisa-Based Adult Heartworm Antigen Test Kits Using Well-Defined Sera From Experimentally and Naturally Infected Cats. Am Assoc Vet Parasitolo- gists 38:37-37, 1993

1 1 8 MATTHEW W. MILLER