Heartworm infection (HWI) (dirofilariasis), caused by Dirofilaria immitis, primarily affects members of the family Canidae. Dirofilariasis is widely distributed, being recognized in northern and southern temperate zones, in the tropics, and in the subtropics. Infections are recognized in most of the United States, although the distribution favors the Southeast and Mississippi River Valley. In some endemic areas in the United States, infection rates approach 45%, and in some hyperendemic tropical regions, virtually all dogs are infected. Dirofilariasis is generally infrequent in Canada. A recent survey of veterinarians indicated that in 2001 there were approximately 240,000 cases diagnosed in the United States.
Species known to have been infected with Dirofilaria immitis include the domestic dog, wolves, foxes, coyotes, domestic cats, ferrets, muskrats, sea lions, nondomestic cats, coatimundi, and humans. The species of greatest interest to die practicing veterinarian include the dog and domestic cat. Because the consequences, treatment, and prognoses differ between the two species, clinical aspects of canine and feline heartworm disease (HWD) will be discussed separately.
When heartworm infection is severe or prolonged, it may result in the pathologic process, called HWD. heartworm disease may vary from asymptomatic (radiographic lesions only) to severe, life-threatening, chronic pulmonary artery, lung, and cardiac disease. In chronic HWI, glomerulonephritis, anemia, and thrombocytopenia may also be recognized. Severe dirofilariasis may, in addition, produce acute and fulminant multisystemic presentations, such as caval syndrome (CS) and disseminated intravascular coagulation (DIC).
Dirofilaria immitis is transmitted by over sixty species of mosquitoes, although important mosquito vectors probably number less than 12. Understanding the complex life cycle of Dirofilaria immitis is imperative for veterinary practitioners in heartworm endemic areas. Adult heartworms (L5) reside in the pulmonary arteries and, to a lesser extent in heavy infections, the right ventricle. After mating, microfilariae (LI) are produced by mature adult female heartworms (L5) and are released into the circulation. These LI are ingested by feeding female mosquitoes and undergo two moults (LI to L2 to L3) over an 8- to 17-day period. It is important to note that this process is temperature dependent; in times of the year when insufficient numbers of days occur in which the ambient temperature is adequate, moulting in the mosquito does not occur during the lifetime of the female mosquito and transmission cannot occur.The resultant L3 is infective and is transmitted by the feeding mosquito to the original or another host, most often a male dog. Another moult occurs in the subcutaneous, adipose, and skeletal muscular tissues shortly after infection (1 to 12 days), with a final moult to L5 3 months (50 to 68 days) after infection. This immature adult (1 to 2 cm in length) soon enters the vascular system, migrating to the heart and lungs, where final maturation (mature male adults range from 15 to 18 cm and females from 25 to 30 cm) and mating occur. Under optimum conditions, completion of the life cycle takes 184 to 210 days. The canine host typically becomes microfilaremic 6 to 7 months after infection. Microfilariae (LI), which are variably present in infected dogs, show both seasonal and diurnal periodicity, with greatest numbers appearing in the peripheral blood during the evening hours and during the summer. Adult heartworms in dogs are known to live up to 5 years and microfilariae up to 30 months. Dillon has recently emphasized that the disease process in heartworm disease begins with the moult to L5 (as soon as 2 to 3 months postinfection), at which time immature adults (L5) enter the vascular system, initiating vascular and possibly lung disease, with eosinophilia and eosinophilic infiltrates and signs of respiratory disease. It is important to note that this antedates the profession’s current ability to diagnose HWI.
Canine Heartworm Disease: Pathophysiology
Heartworm is a misnomer because the adult actually resides in the pulmonary arterial system for the most part, and the primary insult to the health of the host is a manifestation of damage to the pulmonary arteries and lung. The severity of the lesions and hence clinical ramifications are related to the relative number of worms (ranging from one to over 250), the duration of infection, and the host and parasite interaction. Immature and mature adult heartworms reside primarily in the caudal pulmonary vascular tree, occasionally migrating into the main pulmonary arteries, the right heart, and even the great veins in heavy infections.
Obstruction of pulmonary vessels by living worms is of little clinical significance, unless worm burdens are extremely high. The major effect on the pulmonary arteries is produced by worm-induced (toxic substances, immune mechanisms, and trauma) villous myointimal proliferation, inflammation, pulmonary hypertension (PHT), disruption of vascular integrity, and fibrosis.This may be complicated by arterial obstruction and vasoconstriction caused by dead worm thromboemboli and their products. Pulmonary vascular lesions begin to develop within days of worm arrival (as early as 3 months postinfection), With endothelial damage and sloughing, villous proliferation, and activation and attraction of leucocytes and platelets. The immigration of such cells and the release of trophic factors induce smooth muscle cell proliferation and migration with collagen accumulation and eventual fibrosis. Proliferative lesions eventually encroach upon and even occlude vascular lumina. Endothelial swelling with altered intracellular junctions increases the permeability of the pulmonary vasculature. Worms, which have died naturally or have been killed, elicit an even more severe reaction, inciting thrombosis, granulomatous inflammation, and rugous villous inflammation. Grossly, the pulmonary arteries are enlarged, thick-walled, and tortuous, with roughened endothelial surfaces. These changes are only partially reversible.
Although the role of exercise in exacerbation of the signs of thromboembolic heartworm disease is accepted, its role in the development of pulmonary vascular disease and pulmonary hypertension is less clear. Although Rawlings was unable to show an effect of 2.5 months controlled treadmill exercise on pulmonary hypertension in heavily infected dogs, Dillon showed more severe pulmonary hypertension in lightly infected, mildly exercised dogs than in more heavily infected but unexercised dogs receiving no exercise at 6 months postinfection.
Diseased pulmonary arteries are thrombosed, thickened, dilated, tortuous, noncompliant, and functionally incompetent, thereby resisting recruitment during increased demand; hence exercise capacity is diminished. Vessels to the caudal lung lobes are most severely affected. Pulmonary vasoconstriction results secondary to vasoactive substances released from heartworms. Furthermore, hypoxia (induced by ventilation-perfusion mismatching secondary to eosinophilic pneumonitis, pulmonary consolidation, or both), further contributes to vasoconstriction. The result is pulmonary hypertension and compromised cardiac output. Pulmonary hypertension is exacerbated with exercise or other states of increased cardiac output. The right heart, which is an efficient volume pump but does not withstand pressure overload, first compensates by eccentric hypertrophy (dilatation and wall thickening) and, in severe infections, ultimately decompensation (right heart failure). In addition, hemodynamic stresses, geometric changes, and cardiac remodeling may contribute to secondary tricuspid insufficiency, thereby complicating or precipitating cardiac decompensation. Pulmonary infarction is uncommon because of the extensive collateral circulation provided the lung and because of the gradual nature of vascular occlusion. Because of increased pulmonary vascular permeability, perivascular edema may develop. Although, along with an inflammatory infiltrate, this may be evident radio-graphically as increased interstitial and even alveolar density, in and of itself, it is seemingly of minimal clinical significance and does not indicate left heart failure (in other words, furosemide is not indicated).
Spontaneous or postadulticidal thromboembolization (PTE) with dead worms may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, pulmonary infarction. Dying and disintegrating worms worsen vascular damage and enhance coagulation. Pulmonary blood flow is further compromised and consolidation of affected lung lobes may occur. With acute and massive worm death, this insult may be profound, particularly if associated with exercise. Exacerbation by exercise likely reflects increased pulmonary artery flow with escape of inflammatory mediators into the lung parenchyma through badly damaged and permeable pulmonary arteries. Dillon has suggested that the lung injury is similar to that seen in adult respiratory distress syndrome (ARDS).
Pulmonary parenchymal lesions also result by mechanisms other than post-thromboembolic consolidation. Eosinophilic pneumonitis is most often reported in true occult HWD, when immune-mediated destruction of microfilariae in the pulmonary microcirculation produces amicrofilaremia. This syndrome results when antibody-coated microfilariae, entrapped in the pulmonary circulation, incite an inflammatory reaction (eosinophilic pneumonitis). A more sinister but uncommon form of parenchymal lung disease, termed pulmonary eosinophilic granulomatosis, has been associated with HWD. The exact cause and pathogenesis are unknown, but it is felt to be similar to HWD-related allergic pneumonitis. It is postulated that microfilariae trapped in the lungs are surrounded by neutrophils and eosinophils, eventually forming granulomas and associated bronchial lymphadenopathy.
Antigen-antibody complexes, formed in response to heart-worm antigens, commonly produce glomerulonephritis in heartworm-infected dogs. The result is proteinuria (albu-minuria) but uncommonly renal failure. Heartworms may also produce disease by aberrant migration. This uncommon phenomenon has been associated with neuromuscular and ocular manifestations, because worms have been described in tissues such as muscle, brain, spinal cord, and anterior chamber of the eye. In addition, arterial thrombosis with L5 has been observed when worms migrate aberrandy to the aortic bifurcation or more distally in the digital arteries. Adult heartworms may also migrate in a retrograde manner from the pulmonary arteries to the right heart and venae cavae, producing CS, a devastating process, described following.
Clinical Signs of Canine Heartworm Disease
The clinical signs of chronic heartworm disease depend on the severity and duration of infection and, in most chronic cases, reflect the effects of the parasite on the pulmonary arteries and lungs, and secondarily, the heart. It is important to point out that the vast majority of dogs with heartworm infection are asymptomatic. Historical findings in affected dogs variably include weight loss, diminished exercise tolerance, lethargy, poor condition, cough, dyspnea, syncope, and abdominal distension (ascites). Physical examination may reveal evidence of weight loss, split second heart sound (13%), right-sided heart murmur of tricuspid insufficiency (13%), and cardiac gallop. If right heart failure is present, jugular venous distension and pulsation typically accompanies hepatosplenomegaly and ascites. Cardiac arrhythmias and conduction disturbances are uncommon in chronic heartworm disease (<10%). With pulmonary parenchymal manifestations of HWD, cough and pulmonary crackles may be noted and, with granulomatosis (a rare occurrence), muffled lung sounds, dyspnea, and cyanosis are also reported. When massive pulmonary thromboembolization occurs, the additional signs of fever and hemoptysis may be noted.
The prognosis for asymptomatic heartworm infection is generally good and, although the prognosis for severe heartworm disease has to be guarded, a large percentage of such cases can be successfully managed. Once the initial crisis is past and adulticidal therapy has been successful, resolution of underlying manifestations of chronic heartworm disease begins. The prognosis is poorest with severe DIC, CS, massive embolization, eosinophilic granulomatosis, severe pulmonary artery disease, and heart failure After adulticidal therapy, intimal lesions regress rapidly. Improvement is noted as early as 4 weeks post-treatment in the main pulmonary artery, with all pulmonary arteries having undergone marked resolution within 1 year. Radiographic and arteriographic lesions of heartworm disease begin to resolve within 3 to 4 weeks, and pulmonary hypertension is reduced within months and may be normal within 6 months of adulticide therapy. Pulmonary parenchymal changes are worsened during the 6 months after adulticidal therapy and then begin to lessen in severity, with marked resolution within the next 2 to 3 months. Persistence of such lesions is suggestive of persistent infection. Corticosteroid therapy hastens the resolution of these lesions. Likewise irreversible renal disease is uncommon, with glomerular lesions resolving within months of successful adulticidal therapy. Signs of heart failure are also reversible with symptomatic therapy, cage rest, and successful clearing of infection.
Macrolides As Adulticides
It is now proven that ivermectin (and possibly selamectin) has adulticidal efficacy that can approach 100% with prolonged, continuous administration. Ivermectin was demonstrated to be successful as an adulticide in experimental, young infections with 31 months’ continuous administration. The exact role of macrolides in the management of HWI, other than as preventatives, is unclear and likely to be a major controversy in upcoming years.
The appeal of macrolides for this use is that it takes the veterinarian out of the complication loop. Complications might indeed still occur but would not likely be temporally linked to the macrolide administration (as they are to arsenic use). In addition, reduced cost, patient discomfort, and inconvenience are appealing. Arguments against the use of ivermectin in this way include the following:
• Represents an off-label use of ivermectin
• Requires continuous more than 30 months’ compliance from a client that often has allowed heartworm infection to occur — often by poor compliance
• Lack of knowledge about the timing and degree of exercise restriction necessary; safe use might require 31 months of continuous exercise restriction
• Absence of a controlled kill as seen with melarsomine, reducing the ability to effectively monitor for adverse effects
• Lack of knowledge as to the effect of chronic antigen release from slowly dying adult heartworms on the kidneys and lungs
• Knowledge that macrolide “slow adulticidal therapy” does not alleviate the lung disease associated with HWI
• Fact that proven efficacy is only in young (<8 months old) experimental HWIs
• Concern that heartworm resistance to ivermectin might develop in dogs treated in this manner
At the 2001 American Heartworm Symposium, the audience and a panel of experts were polled as to their belief as to the role of ivermectin as an adulticide in their own practices. Five percent of the audience and none of the expert panelists used only ivermectin for adulticidal therapy. Approximately one third of both groups did not or would not use ivermectin as an adulticide under any circumstances. Finally, approximately 70% of the expert panel and 50% of the audience stated that they would use ivermectin for this purpose only under mitigating circumstances of financial or medical constraint.
The author recommends that melarsomine be the primary adulticidal tool and recommends or accepts the use of ivermectin in instances where a preventative is necessary in a heartworm-positive dog and the owner cannot afford arsenic therapy or in which medical conditions preclude its use; in the event of residual infection after appropriate treatment with melarsomine (assumes low worm burden); and, obviously, in unrecognized infections.