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Clinical Significance of Feline Heartworm Disease
ADVANCES IN CARDIOVASCULAR DIAGNOSTICS AND THERAPY
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CLINICAL SIGNIFICANCE OF FELINE HEARTWORM DISEASE Ray Dillon, DVM, MS
The clinical signs and diagnostic approach of feline heartworm disease are different in the cat as compared with the dog, which has impaired the veterinarian's ability to detect this parasite in the cat. New techniques and methodologies have enabled the cat owner and veterinarian to better recognize this potentially severe disease. Although much is now known about the pathophysiology and biology of this parasite in the cat,8• 9• 11 • 19• 36 the rapid development of this information has led to confusion in the practical application. RISK FACTORS
Cats are at risk for heartworm disease if there are dogs in the area with heartworms. Because cats become infected after a mosquito bites a dog and then bites a cat, the feeding pattern of different species of mosquitoes dictates the incidence of feline heartworm disease (FHD) as compared with canine heartworm infections. There is no age predilection for Dirofilaria immitis infection in cats, and a wide age range of clinically infected cats has been reported (6 months to 17 years). Indoor and outdoor cats have been treated for FHD. 1• 4• 7 In a clinical survey of 215 cats that presented with coughing, vomiting, or dyspnea, as determined by owner surveys, 11% of the antibody-positive cats were reported to live indoors 100% of the time and 35% to live outdoors 10% of the time. 33 The infection of indoor cats may reflect an altered feeding pattern
From the Department of Small Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, Alabama
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 28 • NUMBER 6 • NOVEMBER 1998
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Figure 1. Cat heart with opened right ventricle showing one adult female heartworm. This cat had been asymptomatic until presented for acute dyspnea .
of the vector or increased susceptibility of a heartworm naive cat to infection 19 (Fig. 1). Experimentally, male cats have been shown to be more susceptible than female cats and harbor a higher worm burden when infected?· 25 The increased risk for male cats has not been consistently noted in clinical studies. Feline leukemia virus infection is not a predisposing factor, and heartworms are not a common incidental finding ?
CLINICAL SIGNS
The clinical signs are dependent on the stage of the heartworm life cycle: immature LS larvae, adult heartworms, death of heartworms, and permanent lung injury after worm removal. Infected cats may die acutely, exhibit chronic signs, or be asymptomatic (Table 1). The arrival of immature heartworms in the lungs and the death of
Table 1. CLINICAL SIGNS OF FELINE HEARTWORM DISEASE Chronic Signs
Acute Signs
Coughing Dyspnea Vomiting Lethargy Weight loss
Convulsions Vomiting/diarrhea Collapse Blindness Anorexia Tachycardia Syncope
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adult heartworms are the stages most likely to be associated with early clinical signs. The initial arrival (as early as 100 days after infection) of L5 larvae in the distal pulmonary arteries induces a diffuse pulmonary infiltrate and signs typical of "eosinophilic pneumonitis."20• 41 The initial respiratory clinical signs, which the eat's owner may report as coughing, occur most frequently in the 4 to 7 months after the exposure (Figs. 2 and 3). At this time, because the worms are immature, antigen tests are
Figure 2. Lateral radiograph of caudal lung lobes demonstrating diffuse interstitial and bronchial pattern associated with early heartworm infection (L5) approximately 4 months after L3 infection. Cat will often be presented for coughing, and clinical signs and radiographs will improve with corticosteroid therapy. Figure 3. Closer view of Figure 2.
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negative, but most cats will be antibody positive. After the initial host response, the signs may abate and become subclinical for a period of time. Based on cardiopulmonary changes and experimental studies, most heartworm-infected cats, even those with severe heartworm disease, are asymptomatic once the infection becomes established. 10' n, 37 However, the subsequent death of adult heartworms may cause additional severe signs. In the acute cases, death may be so rapid as to preclude diagnosis or treatment. Sudden death has been attributed to circulatory collapse and respiratory failure from acute pulmonary arterial infarction and acute lung injury. 11 Acute collapse may occur with or without previous clinical signs, and only one worm can be responsible for the injury. Cats that die from heartworms can be clinically normal 1 hour before death? All cats in heartworm-endemic areas that die acutely from unknown causes should be examined for heartworm disease. In acute cases, sometimes only one worm has been found to be the cause of severe pulmonary congestion and edema. The worms in the acute syndrome can reside in the distal pulmonary arteries, most often the left and right caudal pulmonary arteries. Although less common, the aberrant location of immature L5 larvae or adult worms has been associated with neurologic signs. 16 Seizures, head tilt, blindness, ataxia and acute vestibular syndrome have resulted from experimental infections9 ' 16 and have been identified in clinically infected cats. 5' 7, 27 Presentation of acute posterior paresis from an aortic location has been observed but is thought to be rare. The novelty of unusual presentations of cats with FHD has tainted the literature relative to the true nature of the spontaneous disease. HISTORY
The most common historical complaints in cats with clinical signs are coughing, dyspnea, vomiting, lethargy, anorexia, and weight loss 7' 13' 21 (Table 1). In a clinical survey of 215 cats presented to 15 practices in the southeastern United States for signs of FHD, the antibody-positive cats (n = 92) presented with coughing (39%), vomiting (24%), and both vomiting and respiratory signs (34%). 33 Vomiting and respiratory signs are the predominate complaints in FHD. Vomiting of food and/ or foam tends to be sporadic and usually unrelated to eating. The etiology of vomiting in heartworm-infected cats is unknown, although the release of inflammatory mediators from the lungs that stimulate the chemoreceptor trigger zone has been hypothesized_?, 10 Supporting this concept is the clinical observation that low doses (2.5 to 5 mg of prednisolone every other day) usually prevent the vomiting. The vomitus generally contains food or foam and is rarely bile stained. Retching and severe paroxysmal vomiting are rare historical findings. Heartworm disease should be included in the differential diagnosis of chronic emesis in the cat. The most common respiratory complaints are coughing and inter-
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mittent dyspnea. Hemoptysis is occasionally noted. The coughing can be in severe paroxysmal attacks. Periods of normalcy (days to weeks) is often observed between episodes. The coughing is usually temporarily corticosteroid responsive, with exacerbation and acute dyspnea still a risk. Chylothorax has been noted but is not a common feature at presentation. The clinical presentation, radiographic pattern, and response to therapy often lead to a tentative diagnosis of bronchial asthma?· 21 • 34 The acute dyspnea may be a result of acute lung injury, especially when associated with worm death. On occasion, occlusion of a pulmonary artery (right caudal being the most common) is accompanied by a radiographic appearance of lung lobe consolidation and the development of life-threatening acute dyspnea. 2• 8• 11 The nonspecific clinical signs are consistent with many feline diseases. Anorexia and/ or lethargy can be the only presenting signs in heartworm cats. In these cases, heartworm disease is often an incidental finding on thoracic radiographs during diagnostic screening. Cats with worms found in abnormal locations may have signs attributable to local pathology. Neurologic signs are uncommon but can occur in infected cats with or without worms in the central nervous system?· 14• 16 The residual damage associated with FHD is difficult to document clinically or experimentally. Few long-term studies have addressed FHD. 9 The author has evaluated clinically infected cats with FHD 1 to 2 years after becoming antibody negative, and these cats continue to have radiographic evidence of peribronchial disease and require corticosteroid therapy to prevent coughing. The relationship between bronchial asthma and elimination of the heartworms remains unanswered. Proteins of excretory/secretory materials from heartworms have been associated with increased lymphocyte cytokine production and increased immunoglobulin response to vaccine challenge in cats. 42 PHYSICAL EXAMINATION
The physical examination is usually normal in Dirofilaria immitisinfected cats. A systolic murmur over the tricuspid valve area and occasionally a gallop rhythm can be present, but generally these findings are uncommon. 14 In cats presenting with murmurs, only 9% were positive for heartworms. 14 Harsh lung sounds (dry rales) are the most frequent abnormal auscultatory finding and can be present in cats without respiratory signs. Ascites, chylothorax, exercise intolerance, and signs of right-sided heart failure are rare. There does not seem to be a correlation between the clinical signs, physical findings, and radiographic findings. DIAGNOSIS
Unlike the diagnostic approach in dogs, the diagnostic modalities are less clearly defined and none are without exception. If one defines
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FHD related to the life cycle, diagnostic findings can change chronologically (Table 2).
Complete Blood Counts
Routine complete blood counts may demonstrate a mild anemia (23% to 33% hematocrit), occasionally nucleated red blood cells, and basophilia (rare). Anemia is present in about one third of infected cats and is nonregenerative, as in heartworm-positive dogs. Peripheral eosinophilia, present in about one third of client cats at the time of diagnosis, is an inconsistent finding even on serial samples in the same cat and is dependent on the stage of the infective larvae. The eosinophilia typically occurs 4 to 7 months postinfection and intermittently thereafter. 9 The absence of eosinophilia does not exclude a diagnosis of feline heartworms. Cytology of bronchial alveolar lavage fluid may contain eosinophils without the presence of a peripheral eosinophilia. As in the dog, the presence of basophilia is highly suggestive of heartworm disease. 10• 13• 33
Tracheal Cytology
The finding of eosinophils on cytologic evaluation of tracheal lavage is common in heartworm disease, asthma, and parasitic lung diseases. 9 However, it also has been noted in healthy cats. 28 In FHD, the presence of eosinophils in the lavage seems to occur 4 to 7 months after L3 larva infection and may not be present later in the infection, even when adult worms are presenU Tracheal cytology typical of chronic inflammation may be present after the eosinophilic reaction resolves. Careful fecal examination should be performed before the lavage. Fecal flotation and direct smears may reveal the large operculated egg of Paragonimus kellicotti or the larvae of Aelurostrongylus abstrusus.
Table 2. DIAGNOSTIC TESTING FOR SUSPECTED FELINE DIROFILARIASIS
CBC Microfilaria detection Blood chemistries and urinalysis Thoracic radiographs Fecal examination EKG Echocardiography Serology for feline antibody against adult antigen Serologic detection of adult antigen Tracheal lavage or BAL Arteriogram
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Blood Chemistries and Urinalysis
Results of blood chemistries and urinalysis are usually normal. Although hyperglobulinemia does occur in some heartworm-infected cats, it is neither consistent nor predictable and should not be used to rule out FHD. Proteinurea has not been associated with FHD. 10 One cat with heartworms reportedly developed unilateral eosinophilic nephritis presumed to be associated with aberrant migration of larvaeY Microfilaria Detection
Experimental infections produced via L3 larvae or transplantation of adults usually result in a microfilaremia of short duration and low numbersP· 25 Concentration tests such as Knott tests or Millipore filter techniques are best. In North and South America, the only filarial disease of cats is heartworms; therefore, any microfilaria observed should be considered D. immitis. Serology
The confusion over the interpretation of the different tests and the variability of the methodology of individual laboratories has caused the practicing veterinarian problems in making a definitive diagnosis. With the high incidence of occult disease in the cat, the use of serology is a valuable asset. Three serologic methods have been used to assess FHD: 1. Immunofluorescence (IFA) for microfilarial antibody 2. Detection of host antibody against adult 3. Adult antigen detection by ELISA and colloid gold
Immunofluorescence Testing
Application of the canine IFA test (detecting antibodies to microfilarial cuticular antigen) was useful in early research and approximately diagnostic in about 33% of cats with adult heartworms,l 5 but the presence of immature or sterile worms, worms of only one sex, or the absence of host response to antigen does not produce a diagnostic titer. 15• 34 These assays have been helpful in researching the biology of the parasite-host interaction but have limited application to clinical diagnostics. Use of anti-D. immitis antibody to somatic antigens recently was reintroduced but has not been independently validated. Antibody Detection
The detection of feline antibodies to adult heartworm antigen has advantages over antigen testing in cats that demonstrate clinical signs
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consistent with FHD. Initial concerns related to false-positive results from cross-reactivity have not been observed. Initial studies of cats that have eliminated the adult parasite naturally or after adulticide reveals that a negative titer develops when the host antibody gradually decreases to negative concentrations (4 to 6 months). The antibody denotes a method of analysis; therefore, antigen preparation, antibody sources, and techniques can vary between diagnostic laboratories, and titers may differ accordingly. Because the antibody being detected is produced by the cat in response to the early migration of the L3 or L4 larvae, positive titers are detected about 2 to 3 months after a successful infection in about 50% of cats and is consistently positive by 5 months. 25, 26, 29, 34 Detection of antibodies in symptomatic cats does confirm a successful infection of the L3-L4 stages. However, with the use of macrolides as a preventative medication, the larvae in a cat can initiate a positive antibody response and then can be killed by the macrolide, leading to an antibody-positive but heartworm-negative outcome. Additionally, the death of adult heartworms may produce a strong antibody response after release of large amounts of antigen. 9 Some of the highest titers are associated with severe clinical signs in cats in which the worms have died and in which the disease may be resolving. 10 In rare cases, the antibody test result can be negative even in the presence of adult worms. Of the different antibody tests currently available, there are differences in the antibody that each appears to quantitate. There appears to be no correlation between antibody levels and the number of worms or severity of disease in the initial studies based on antibody titers by Animal Diagnostics Inc, St. Louis, Missouri. Detection of high concentrations of antibody to a specific heartworm antigen by Heska Co., Fort Collins, Colorado, has been noted in some cats with larger adult worm burdens. The author has observed confirmed cases of heartworms that are antibody negative by all current assays. Early evidence suggests that during an active heartworm infection, the currently available antibody detection methods are triggered by different antigens; thus, discordant results between two antibody testing methods should not surprise the veterinarian. Serial testing frequently yields a negative test that becomes positive 1 to 3 months later. Based on initial impressions, after an L3 larva infection, the polyclonal antibody detected by Animal Diagnostics is noted 1 to 2 months before the antibody detected by Heska Co. Although this indicates early infection, neither test result indicates adult infection. A positive antibody result shows that the cat has been successfully infected with L3larvae, that an L4 molt has occurred, and that the larvae have lived at least 2 to 3 months and may or may not have developed into adult heartworms. 25' 26 The duration of continued antibody response in a cat with a chronic adult infection (i.e., a cat with a 2-year-old heartworm) cannot be confirmed using all testing methods at this time. Because the antibody detection is specific for feline antibody, these methods cannot be used in other species.
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Antigen Testing
Heartworm antigen detection tests using blood or serum have been successful in dogs, and results have been positive in cats within days of transplantation of mature adult worms from dogs into cats. 10• 14 Because the majority of antigen being detected is derived primarily from the adult female reproductive tract, immature infections, a low worm burden, male-only infections, or sexually immature worms will not produce enough antigen to be detected. The elimination of the adult parasite also causes a negative antigen test. Early evidence suggests that new antigen detection methods may detect different antigens and may become positive before the typical 6- to 8-month interval after L3 larva infections. Cats may test positive for antigen 6 to 8 months after the experimental infections with large numbers of L3 larvae. 24-26 However, clinically infected cats and experimentally infected cats with active heartworm disease and high antibody titers can test negative for antigen. The low heartworm numbers in clinical infections and the clinical signs associated with immature worms make it prudent to consider a positive antigen test result diagnostic but not to rule out heartworms based on a negative antigen test result. Most cats with heartworm disease are antigen negative. Of the different assays for antigen in the blood, each should be reviewed for strengths and weaknesses. Data would support the basic consideration that a microwell titer technology on serum is best for detecting low antigen concentrations. Electrocardiography
Although subtle signs of right ventricular enlargement are occasionally noted (with unipolar chest leads) a right axis vector (>120°) on a standard six-lead EKG is rare. Ectopic ventricular beats and other arrhythmias have been observed infrequently after adulticide in asymptomatic cats. 10 Radiography
The pulmonary parenchymal changes are nonspecific and can change rapidly in infected cats. 9• 10• 20• 31- 33• 37 The lung lesions include diffuse or coalescing infiltrates, perivascular densities, and lung atelectasis. The most distinctive radiographic sign is enlarged pulmonary arteries with ill-defined margins, most prominent in the caudal lung lobes on the VD view (Fig. 4). Blunting and tortuosity of the pulmonary arteries are seen occasionally, but these findings are not as common in cats as in dogs. An enlarged main pulmonary arterial segment extending beyond the cardiac border on the VD or DV view is not a classic feature of feline heartworms. The enlargement of the caudal pulmonary artery may disappear over a period of several months. Some cats with heartworm disease have normal radiographic results. Severe infiltrative disease also may inhibit visualization of the pulmonary arteries. After an
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Figure 4. Enlargement of the right caudal pulmonary artery can be visualized beyond the edge of the cardiac shadow and is consistent with heartworm infections, but this lesion is not present in many cats with active adult infections.
acute episode, a lung lobe (left caudal, right caudal, or right middle) may appear consolidated (Fig. 5). The pulmonary interstitial edema and hemorrhage is often corticosteroid responsive? Atelectasis of the right middle lung lobe appears to be less likely to resolve and may become permanent. Arteriograms as a diagnostic tool may demonstrate the enlarged pulmonary arteries and embolus31 (Fig. 6). Nonselective angiocardiography is a simple and safe method of confirming a tentative diagnosis of heartworms. A radiographic exposure 5 to 6 seconds after injection of contrast material into the jugular vein will provide good visualization of the pulmonary vasculature and on occasion the presence of worms. There does not seem to be a correlation between the severity of lesions based on angiocardiographic results and the severity of clinical signs or postadulticide reaction. Because of the changing nature of the disease over time, repeated radiographs are often necessary. Echocardiogram
Parallel hyperechoic lines, representing an image from the heartworm cuticle, may be observed in the pulmonary arteries, right ventricle, or, rarely, the right atria. 6• 37• 39 • 40 These lines are generally not over 0.5 to
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Figure 5. Acute signs in this heart· worm cat was associated with acute lung injury of the left caudal lung lobe especially. The resultant pulmonary inflammation made identification of caudal pulmonary arteries difficult. Radiographic visu· alization of acute pulmonary lesions as in this radiograph may not be observed until 1 to 2 days after the acute crisis.
Figure 6. Nonselective angiogram is useful in identifying enlarged or occluded pulmonary arteries associated with heartworm disease. Cat heartworms can rarely be visualized.
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Figure 7. Gross examination demonstrates the nature of the acute pulmonary inflammation associated with this cat. One live female and 1 dead male heartworm was identified.
1 em in length because of the angle of the probe and curved nature of the worms in the heart. Heartworms in the most distal pulmonary arteries often cannot be visualized. Echocardiography is useful to confirm a tentative diagnosis of heartworms6• 39 (Fig. 7). The right parasternal view gives the best vantage point of the pulmonary outflow tract.39 The most common location of the adult worm is the pulmonary outflow tract. 6• 39 In the hands of an experienced individual, echocardiography in cats is diagnostic in over half the cases of FHD. Differential Diagnosis
In the cat with respiratory signs, heartworm disease must be differentiated from Aelurostrongylus abstrusus or Paragonimus kellicotti infection, asthma, cardiomyopathy, and other diseases associated with dyspnea (e.g., pyothorax, pleural effusions, pneumothorax, FIP, lymphosarcoma, and anemia)?· 10 Although each in various stages can mimic the clinical and radiographic pulmonary parenchymal changes, the pulmonary arterial changes of heartworm disease are unique, if present, and can be enhanced by contrast procedures. The changing clinical and radiographic pattern of disease make the diagnosis difficult, and over time there will be differences in diagnostic results. The peripheral eosinophilia, eosinophilic tracheal cytology, and chronic cough of feline heartworms is consistent with a diagnosis of "bronchial asthma." However, an apparent higher incidence of asthma has not been reported in heartworm-endemic areas. The enlarged pulmonary arteries and muscular hypertrophy of Aelurostrongylus abstrusus and Toxocara cati infection is clinically uncommon. CLINICAL MANAGEMENT OF FELINE HEARTWORM DISEASE
After the diagnosis of FHD, the veterinarian and client are in a lose-lose situation. Conservative management would be to hope that
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the adult worms die spontaneously over the next months to years and to endure the risk of continued chronic problems and/or an acutecrisis. The aggressive approach would include the use of an adulticide to eliminate the worms, risking the severe consequences of acute complications associated with the worm(s) dying at one time. Because of the dire consequences of management of FHD, preventative medication for cats is recommended if heartworm-infected dogs are in the area. Therapy for Heartworm-Positive Cats
Owners' attitudes dictate the approach. Because feline heartworminfected cats are often asymptomatic or demonstrate only chronic vomiting or intermittent respiratory signs, the owner must be reminded that this is a serious disease. Owners should be reminded that spontaneous acute complications and death do occur in a small percentage of cats with heartworms. No relationship has been detected between the clinical signs and risk of acute complications (Fig. 8). Because the adult heartworm has a shortened longevity in the cat as compared with the dog, the possibility of spontaneous recovery also should be discussed. The concept that heartworms do not live normal 5-year life spans in cats does not rule out the occasional cat that continues to have adult infections for 3 to 4
Figure 8. Echocardiogram demonstrating hyperechoic parallel lines (arrow) in right ventricle as the cuticle of a heartworm is visualized. The most common location is the right ventricle and main pulmonary arteries.
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years. Although, the natural death of the adult worms can be associated with severe respiratory signs, most cats recover without severe complications. Cats, managed conservatively by intermittent corticosteroid therapy, still are at risk for acute signs. In the cat with recurrent dyspnea that is life-threatening or with clinical signs that are unacceptable to the owner, adulticidal therapy has been used safely and should be considered. Adulticidal Therapy
Treatment of FHD with thiacetarsamide sodium (2.2 mg/kg intravenously twice daily for 2 days) is tolerated by cats without immediate complications of hepatotoxicity or renal toxicity. 10• 13 Concerns as to a direct acute lung injury from thiacetarsamide in normal cats causing pulmonary edema and respiratory failure 39 could not be reproduced in studies in 12 normal cats. 12 The use of ketamine as a sedative to aid in careful administration of thiacetarsamide is recommended in active cats. There are occasional reports of acute symptoms after thiacetarsamide injections, but slow injections have not caused acute collapse in normal healthy cats in this author's experience?· 8 Although the presence of circulating microfilaria is uncommon, ivermectin has been used successfully as a microfilaricide. Postadulticida/ Complications
Complications after therapy are usually related to acute lung injury associated with dying heartwormsY· 21 Sudden death from respiratory failure can occur, especially within the first 10 days after adulticide administration. Embolization can induce severe lung injury, hemoptysis, and dyspnea. Severe thrombocytopenia and disseminated intravascular coagulation have not been noted. Based on the assumption that heartworm mass is related to antigen load, a cat with a strongly positive antigen test result would be more likely to develop postadulticide complications. Worm death most often affects the caudal lung lobes, and thoracic radiographs may demonstrate a lung lobe with increased density. Oxygen therapy is indicated if dyspnea occurs. High doses of corticosteroids (1 to 2 mg/kg of prednisolone) with careful IV fluid therapy will often support the cat through the crisis. The routine use of corticosteroids is not recommended before or after thiacetarsamide in cats. Aspirin is not indicated in FHD. 31 • 32 Because of the potential protective effects of ketamine as a serotonin antagonist, a single intramuscular injection of ketamine has been recommended before administration of the first dose of thiacetarsamideP The acute nature of the postadulticide reaction dictates that the cat be under 24-h/ day observation, especially during the first 2 weeks. The clinical and radiographic signs of acute embolization can resolve over 1 to 2 days. However, death can occur before therapy can be instituted. The client should be aware that the risk of complications in the cat seems to be greater than in the dog. The
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severity of the postadulticidal reaction poses a dilemma for the veterinarian, and the risk of postadulticide complications is probably greater than the risk of spontaneous death in the asymptomatic, heartworminfected cat. The advantage of treating a cat is being able to observe the cat during the 2-week period after thiacetarsamide therapy while the worms are dying, compared with waiting for the spontaneous death of worms. However, adulticidal therapy in one study did not increase the mean survival time in cats administered an adulticide compared with those treated conservatively. 1 Owners should be advised that 30% of cats receiving adulticidal therapy will have a life-threatening crisis within 3 weeks of therapy_?, 10 Efficacy of Treatment
The efficacy of thiacetarsamide cannot be evaluated in many client cats because of the occult nature of the disease. However, current research seems to indicate that the adulticide is effective and clinical signs usually abate during the initial weeks after thiacetarsamide, 30 Based on data from studies on dogs, immature worms are probably resistant to thiacetarsamide. If a cat was antigen positive before therapy, the antigen test result should be negative 12 weeks after successful adulticide therapy. Data on imiticide use in FHD is limited, but antidotal reports would advise against using the dog protocol. Surgical Therapy
Removal of heartworms via jugular venotomy has been used successfully with an endoscopic basket3 and by wrapping the heartworms with horsehair brushes or Swan-Ganz balloon flotation catheters. More invasive is a thoracotomy and removal of the heartworms by right ventricular incision or pulmonary arteriotomy. Invasive surgery should be reserved for cats with heartworms that have been visualized by echocardiography. Conservative Therapy
The owner should be educated as to the nature of the peracute signs of heartworm disease. Alternate day prednisolone therapy (2 to 5 mg/ kg) has been used successfully to prevent clinical signs of coughing and vomiting. However, progression of radiographic lesions has been observed during corticosteroid therapy. In addition, acute respiratory distress and death have occurred in cats on conservative glucocorticoid therapy. An emergency dose of oral or injectable glucocorticoid should be dispensed to the owner to be administered if collapse or dyspnea are noted. The onset of acute respiratory signs in a heartworm cat is a true emergency requiring immediate care. The radiographic signs of severe lung pathology should not be overinterpreted as "consolidation or pneumonia." The initiation of intranasal oxygen therapy, cage rest, small
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volumes of intravenous fluids, and injectable prednisolone (100 to 250 mg prednisolone sodium succinate IV) has resulted in clinical improvement and resolution of radiographic signs within 24 hours of presentation in cats with life-threatening dyspnea and collapse. Subtle respiratory signs should be treated aggressively in heartworm-positive cats. Serial antibody testing (6-month intervals) can be used to assess the heartworm status. Generally, cats that have eliminated the adult infection will be antibody negative 6 to 9 months after all adults worms have been removed (Fig. 9). Preventative Medication
In endemic areas with vector populations (dogs) providing the mosquito with a reservoir, the incidence of heartworms in cats and the dire consequences of the infection indicate that preventive medication is warranted. Studies in most endemic areas indicate an infection rate, based on necropsy data, of 2.5% to 16%, with a median of 7%.34• 35 The antibody test reflects successful infection of L3 larvae, molting to L4 larvae, and survival for at least 2 to 3 months. Of 215 cats presented to 15 practices in the southeastern United States with vomiting or respiratory signs, 43% were antibody positive, and 11% lived indoors 100% of the time and 35% lived outdoors less than 90% of the time.33 In this
Figure 9. Chronic lesions associated with cats after heartworm disease can be collapse of a lung lobe that does not reinflate (right middle in radiograph) and peribronchial densities. This cat had been antigen- and antibody-negative for 2 years, and corticosteroid medication on an alternate day dosing was required to prevent coughing and occasional dyspneic episodes.
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author's experience and in a study at North Carolina State University/ one third of cats with FHD are considered indoor cats by their owners. Ivermectin (24 J,Lg/kg) 23 and milbemycin (500 J.Lg/kg)3 8 administered per os once a month safely prevent heartworm infections in cats. Heartgard for Cats, (24 J.Lg/kg ivermectin; Merial Limited, Iselin, NJ) has received US Food and Drug Administration approval for use in cats. In endemic areas, it is suggested that preventative medication be administered at 4 to 6 weeks of age and continued for the life of the cat. Although heartworm disease may be of low incidence in many areas, the high rate of complications associated with FHD makes preventative medication an attractive alternative. Because current antigen testing is inconsistent in cats, especially those with a low worm burden, antigen testing before instituting preventative therapy in an adult cat would not seem to be cost effective. Antibody testing would be positive if the cat had been successfully infected and the heartworm had lived at least 2 to 3 months but does not equate with status of adult infections. Furthermore, a heartwormpositive cat even with microfilaria can be safely administered Heartgard for Cats. 23 Regardless of any of the serodiagnostic results, a cat can be safely placed on preventative medication. The diagnostics would aid the owner and veterinarian in knowing the risk of infection in the cat. If either antigen or antibody positive, additional diagnostics could be pursued. The status of diagnostics before preventative medication will continue fo evolve as diagnostic modalities become more refined. After a cat has been on preventative medication, if exposed to L3 larvae, the larvae may live long enough to induce a positive antibody response in the cat but would not develop an adult infection. The antibody test would have limited application in yearly rechecks of cats unless in the future antibody levels can be used to distinguish between precardiac infections and adult infections. Although heartworm disease can be self-limiting in many cats, the potential to initiate inflammatory lung disease and predispose to bronchial asthma may prove to be adequate indications for preventative medications for cats in endemic areas. References 1. Atkins CE, DeFrancesco TD, Miller M, et al: Prevalence of heartworm infection in cats cardiorespiratory abnormalities [Abstract]. J Vet Med 10:161, 1996 2. Benard MA: Acute dirofilarial death. Can Vet J 11:190-191, 1978 3. Borgarelli M, Venco L, Piga PM, Bonino F, Ryan WG: Surgical removal of heartworms from the right atrium of a cat. J Am Vet Med Assoc 211:68, 1997 4. Calvert CA, Mandell CP: Diagnosis and management of feline heartworm disease. J Am Vet Med Assoc 180:565, 1982 5. Cusick PK, Todd KS, Blake JA, et al: D. immitis in the brain and heart of a cat from Massachusetts. J Am Anim Hosp Assoc 12:490, 1976 6. DeFrancesco TD, Atkins CE, Meurs K: Diagnostic utility of echocardiography in heartworm disease [Abstract]. J Vet Intern 11:141, 1997
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7. Dillon AR: Feline heartworms: More than just a curiosity. Vet Forum Dec:18, 1995 8. Dillon AR, Warner AE, Molina R: Dirofilaria immitis infection in dogs and cats results in pulmonary airway epithelial and microvascular injury. J Vet Intern Med 7:119, 1993 9. Dillon AR, Brawner WR, Grieve RB, et al: The chronic effects of experimental Dirofilaria immitis infection in cats. Vet Med Surg 2:72, 1987 10. Dillon AR: Feline heartworm disease. In Fox, Sisson (eds). Canine and Feline Cardiology. Philadelphia, WB Saunders, in press 11. Dillon AR, Warner AE, Molina RM, Soli MD, Knight DH: Pulmonary parenchymal changes in dogs and cats after experimental transplantation of dead Dirofilaria immitis. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April2. Batavia, IL, American Heartworm Society, 1995, pp 97-101 12. Dillon R, Cox N, Brawner B, D'Andrea G: The effects of Thiacetarsamide administration to normal cats. In Soli MD (ed): American Heartworm Society Proceedings. Batavia, IL, American Heartworm Society, 1994, pp 133-137 13. Dillon AR: Feline dirofilariasis. In Atwell, Bareham (eds): Dirofilariasis. Queensland, Australia, CRC Press, 1988, 205-215 14. Dillon AR: Feline heartworm disease. Vet Clin North Am 14:1185, 1984 15. Dillon AR, Sakas PS, Buxton BA, et al: Indirect immunofluorescence testing for diagnosis of occult Dirofilaria immitis infection in three cats. JAm Vet Med Assoc 180:80, 1982 16. Donahoe JM, Holzinger EA: D. immitis in the brains of a dog and a cat. J Am Vet Med Assoc 164:518, 1974 17. Donahoe JR, Kneller SK, Lewis RE: Hematologic and radiographic changes in cats after inoculation with infective larvae of D. immitis. JAm Vet Med Assoc 168:413, 1976 18. Fowler JL, Matsuda K, Fernan RC: Experimental infection of the domestic cat with D immitis. JAm Vet Med Assoc 19:79, 1972 19. Genchi C, Di Sacco B, Cancrini G: Epizootiology of canine and feline heartworm infections in Northern Italy: Possible mosquito vectors. In Soli MD (ed): American Heartworm Society Proceedings. Batavia, IL, American Heartworm Society, 1994, pp 39-46 20. Holmes RA, Clark JN, Casey HW, et al: Histopathologic and radiographic studies of the development of heartworm pulmonary vascular disease in experimentally infected cats. In Soli MD (ed): Proceedings of the Heartworm Symposium '92. Batavia, IL, American Heartworm Society, 1992, pp 81-89 21. Holmes RA. Feline heartworm disease. Compend Cantin Educ Pract Vet 15:687, 1993 22. Kobayashi Y, Awakura T, Shimada A, Umemura T, Yao M, Sato H. Dirofilariasis in a cat with eosinophilic interstitial nephritis. J Jpn Vet Med Assoc 45:862, 1992 23. Longhoffer SL, Dauria CP, Plue RE, Alva R, Wallace DH, Roncalli RA. Ivermectin for prevention of feline heartworm disease. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 177-182 24. Mansour AE, McCall JW, McTier TL, Supakorndej N, Ricketts R, Soli MD, Knight DH: Epidemiology of feline dirofilariasis. Infections induced by simulated natural exposure to Aedes aegypti experimentally infected with heartworms. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 87-95 25. McCall JW, Nonglak S, Ryan W, Soil MD: Utility of an ELISA-based antibody test for detection of heartworm infection in cats. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 127-133 26. McTier TL, Supakorndej N, McCall JW, Dzimianski MT: Evaluation of ELISA-based adult heartworm antigen test kits. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April 2. Batavia, IL, American Heartworm Society, 1995 27. Otto GF: Abnormal host = abnormal locations. Am Heartworm Soc Bull4:14, 1978 28. Padrid P, Feldman BF, Funk K, Samitz EM, Rei! D, Cross CE: Cytologic, microbiologic, and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 healthy cats. Am J Vet Res 52:1300, 1991
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29. Prieto C Venco L, Simon F, Genchi C: Feline heartworm (Dirofilaria immitis) infection: Detection of specific IgG for the diagnosis of occult infections. Vet Parasitol 70:209, 1997 30. Rawlings CA: Heartworm Disease in Dogs and Cats. Philadelphia, WB Saunders, 1986, pp 329 31. Rawlings CA: Pulmonary arterography and hemodynamics during feline heartworm disease. J Vet Intern Med 4:285, 1990 32. Rawlings CA: Pulmonary arteriography and hemodynamics during feline heartworm disease. J Vet Intern Med 4:285, 1990 33. Robertson C Dillon AR, Brawner W: Clinical study of 215 cats in South Eastern US Practices. Am Assoc Vet Parasitol ??:81, 1997 34. Ryan WG, Gross SJ, Soil MD. Diagnosis of feline heartworm infection. In Soll MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 121-126 35. Ryan WG, Newcomb KM. Prevalence of feline heartworm disease-A global review. In Soll MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 79-86 36. Schafer M, Berry CR. Cardiac and pulmonary artery mensuration in feline heartworm disease. Vet Radio! Ultrasound 36:499, 1995 37. Selcer BA, Newell SM, Mansour MS, McCall JW. Radiographic and 2-D echocardiographic findings in eighteen cats experimentally exposed to D. immitis via mosquito bites. Vet Radio! Ultrasound 37:3744, 1996 38. Stewart VA, Blagburn BL, Hendrix CM, Hepler DI, Grieve RB. Milbemycin oxime as an effective preventative of heartworm (Dirofilaria immitis) infection in cats. In Soll MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 126-131 39. Turner JL, Lees GE, Brown SA, Knauer KW, Yager LM, Edwards JF, Reagor JC: Thiacetarsamide in healthy cats: Clinical and pathological observations. J Am Anim Hosp Assoc 27:275, 1991 40. Venco L, Ghelfi E, Calzolari D, Morini S: Diagnostic techniques (radiography, electrocardiography, ultrasound) in heartworm disease in cats. Vet Cremona 10:23, 1996 41. Wong MM, Pedersen NC, Cullen J: Dirofilariasis in cats. J Am Anim Hosp Assoc 19:855, 1983 42. Zeidner NS, Belasco DL, Dreitz MJ, Frank GR, Usinger WR. Gliding bacterial adjuvant stimulates feline cytokines in vitro and antigen-specific IgG in vivo. Vaccine 13:1294, 1995
Address reprint requests to: Ray Dillon, DVM, MS Department of Small Animal Medicine and Surgery College of Veterinary Medicine Auburn University Auburn, AL 36849
0195-5616/98 $8.00 + .00
CLINICAL SIGNIFICANCE OF FELINE HEARTWORM DISEASE Ray Dillon, DVM, MS
The clinical signs and diagnostic approach of feline heartworm disease are different in the cat as compared with the dog, which has impaired the veterinarian's ability to detect this parasite in the cat. New techniques and methodologies have enabled the cat owner and veterinarian to better recognize this potentially severe disease. Although much is now known about the pathophysiology and biology of this parasite in the cat,8• 9• 11 • 19• 36 the rapid development of this information has led to confusion in the practical application. RISK FACTORS
Cats are at risk for heartworm disease if there are dogs in the area with heartworms. Because cats become infected after a mosquito bites a dog and then bites a cat, the feeding pattern of different species of mosquitoes dictates the incidence of feline heartworm disease (FHD) as compared with canine heartworm infections. There is no age predilection for Dirofilaria immitis infection in cats, and a wide age range of clinically infected cats has been reported (6 months to 17 years). Indoor and outdoor cats have been treated for FHD. 1• 4• 7 In a clinical survey of 215 cats that presented with coughing, vomiting, or dyspnea, as determined by owner surveys, 11% of the antibody-positive cats were reported to live indoors 100% of the time and 35% to live outdoors 10% of the time. 33 The infection of indoor cats may reflect an altered feeding pattern
From the Department of Small Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, Alabama
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 28 • NUMBER 6 • NOVEMBER 1998
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Figure 1. Cat heart with opened right ventricle showing one adult female heartworm. This cat had been asymptomatic until presented for acute dyspnea .
of the vector or increased susceptibility of a heartworm naive cat to infection 19 (Fig. 1). Experimentally, male cats have been shown to be more susceptible than female cats and harbor a higher worm burden when infected?· 25 The increased risk for male cats has not been consistently noted in clinical studies. Feline leukemia virus infection is not a predisposing factor, and heartworms are not a common incidental finding ?
CLINICAL SIGNS
The clinical signs are dependent on the stage of the heartworm life cycle: immature LS larvae, adult heartworms, death of heartworms, and permanent lung injury after worm removal. Infected cats may die acutely, exhibit chronic signs, or be asymptomatic (Table 1). The arrival of immature heartworms in the lungs and the death of
Table 1. CLINICAL SIGNS OF FELINE HEARTWORM DISEASE Chronic Signs
Acute Signs
Coughing Dyspnea Vomiting Lethargy Weight loss
Convulsions Vomiting/diarrhea Collapse Blindness Anorexia Tachycardia Syncope
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adult heartworms are the stages most likely to be associated with early clinical signs. The initial arrival (as early as 100 days after infection) of L5 larvae in the distal pulmonary arteries induces a diffuse pulmonary infiltrate and signs typical of "eosinophilic pneumonitis."20• 41 The initial respiratory clinical signs, which the eat's owner may report as coughing, occur most frequently in the 4 to 7 months after the exposure (Figs. 2 and 3). At this time, because the worms are immature, antigen tests are
Figure 2. Lateral radiograph of caudal lung lobes demonstrating diffuse interstitial and bronchial pattern associated with early heartworm infection (L5) approximately 4 months after L3 infection. Cat will often be presented for coughing, and clinical signs and radiographs will improve with corticosteroid therapy. Figure 3. Closer view of Figure 2.
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negative, but most cats will be antibody positive. After the initial host response, the signs may abate and become subclinical for a period of time. Based on cardiopulmonary changes and experimental studies, most heartworm-infected cats, even those with severe heartworm disease, are asymptomatic once the infection becomes established. 10' n, 37 However, the subsequent death of adult heartworms may cause additional severe signs. In the acute cases, death may be so rapid as to preclude diagnosis or treatment. Sudden death has been attributed to circulatory collapse and respiratory failure from acute pulmonary arterial infarction and acute lung injury. 11 Acute collapse may occur with or without previous clinical signs, and only one worm can be responsible for the injury. Cats that die from heartworms can be clinically normal 1 hour before death? All cats in heartworm-endemic areas that die acutely from unknown causes should be examined for heartworm disease. In acute cases, sometimes only one worm has been found to be the cause of severe pulmonary congestion and edema. The worms in the acute syndrome can reside in the distal pulmonary arteries, most often the left and right caudal pulmonary arteries. Although less common, the aberrant location of immature L5 larvae or adult worms has been associated with neurologic signs. 16 Seizures, head tilt, blindness, ataxia and acute vestibular syndrome have resulted from experimental infections9 ' 16 and have been identified in clinically infected cats. 5' 7, 27 Presentation of acute posterior paresis from an aortic location has been observed but is thought to be rare. The novelty of unusual presentations of cats with FHD has tainted the literature relative to the true nature of the spontaneous disease. HISTORY
The most common historical complaints in cats with clinical signs are coughing, dyspnea, vomiting, lethargy, anorexia, and weight loss 7' 13' 21 (Table 1). In a clinical survey of 215 cats presented to 15 practices in the southeastern United States for signs of FHD, the antibody-positive cats (n = 92) presented with coughing (39%), vomiting (24%), and both vomiting and respiratory signs (34%). 33 Vomiting and respiratory signs are the predominate complaints in FHD. Vomiting of food and/ or foam tends to be sporadic and usually unrelated to eating. The etiology of vomiting in heartworm-infected cats is unknown, although the release of inflammatory mediators from the lungs that stimulate the chemoreceptor trigger zone has been hypothesized_?, 10 Supporting this concept is the clinical observation that low doses (2.5 to 5 mg of prednisolone every other day) usually prevent the vomiting. The vomitus generally contains food or foam and is rarely bile stained. Retching and severe paroxysmal vomiting are rare historical findings. Heartworm disease should be included in the differential diagnosis of chronic emesis in the cat. The most common respiratory complaints are coughing and inter-
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mittent dyspnea. Hemoptysis is occasionally noted. The coughing can be in severe paroxysmal attacks. Periods of normalcy (days to weeks) is often observed between episodes. The coughing is usually temporarily corticosteroid responsive, with exacerbation and acute dyspnea still a risk. Chylothorax has been noted but is not a common feature at presentation. The clinical presentation, radiographic pattern, and response to therapy often lead to a tentative diagnosis of bronchial asthma?· 21 • 34 The acute dyspnea may be a result of acute lung injury, especially when associated with worm death. On occasion, occlusion of a pulmonary artery (right caudal being the most common) is accompanied by a radiographic appearance of lung lobe consolidation and the development of life-threatening acute dyspnea. 2• 8• 11 The nonspecific clinical signs are consistent with many feline diseases. Anorexia and/ or lethargy can be the only presenting signs in heartworm cats. In these cases, heartworm disease is often an incidental finding on thoracic radiographs during diagnostic screening. Cats with worms found in abnormal locations may have signs attributable to local pathology. Neurologic signs are uncommon but can occur in infected cats with or without worms in the central nervous system?· 14• 16 The residual damage associated with FHD is difficult to document clinically or experimentally. Few long-term studies have addressed FHD. 9 The author has evaluated clinically infected cats with FHD 1 to 2 years after becoming antibody negative, and these cats continue to have radiographic evidence of peribronchial disease and require corticosteroid therapy to prevent coughing. The relationship between bronchial asthma and elimination of the heartworms remains unanswered. Proteins of excretory/secretory materials from heartworms have been associated with increased lymphocyte cytokine production and increased immunoglobulin response to vaccine challenge in cats. 42 PHYSICAL EXAMINATION
The physical examination is usually normal in Dirofilaria immitisinfected cats. A systolic murmur over the tricuspid valve area and occasionally a gallop rhythm can be present, but generally these findings are uncommon. 14 In cats presenting with murmurs, only 9% were positive for heartworms. 14 Harsh lung sounds (dry rales) are the most frequent abnormal auscultatory finding and can be present in cats without respiratory signs. Ascites, chylothorax, exercise intolerance, and signs of right-sided heart failure are rare. There does not seem to be a correlation between the clinical signs, physical findings, and radiographic findings. DIAGNOSIS
Unlike the diagnostic approach in dogs, the diagnostic modalities are less clearly defined and none are without exception. If one defines
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FHD related to the life cycle, diagnostic findings can change chronologically (Table 2).
Complete Blood Counts
Routine complete blood counts may demonstrate a mild anemia (23% to 33% hematocrit), occasionally nucleated red blood cells, and basophilia (rare). Anemia is present in about one third of infected cats and is nonregenerative, as in heartworm-positive dogs. Peripheral eosinophilia, present in about one third of client cats at the time of diagnosis, is an inconsistent finding even on serial samples in the same cat and is dependent on the stage of the infective larvae. The eosinophilia typically occurs 4 to 7 months postinfection and intermittently thereafter. 9 The absence of eosinophilia does not exclude a diagnosis of feline heartworms. Cytology of bronchial alveolar lavage fluid may contain eosinophils without the presence of a peripheral eosinophilia. As in the dog, the presence of basophilia is highly suggestive of heartworm disease. 10• 13• 33
Tracheal Cytology
The finding of eosinophils on cytologic evaluation of tracheal lavage is common in heartworm disease, asthma, and parasitic lung diseases. 9 However, it also has been noted in healthy cats. 28 In FHD, the presence of eosinophils in the lavage seems to occur 4 to 7 months after L3 larva infection and may not be present later in the infection, even when adult worms are presenU Tracheal cytology typical of chronic inflammation may be present after the eosinophilic reaction resolves. Careful fecal examination should be performed before the lavage. Fecal flotation and direct smears may reveal the large operculated egg of Paragonimus kellicotti or the larvae of Aelurostrongylus abstrusus.
Table 2. DIAGNOSTIC TESTING FOR SUSPECTED FELINE DIROFILARIASIS
CBC Microfilaria detection Blood chemistries and urinalysis Thoracic radiographs Fecal examination EKG Echocardiography Serology for feline antibody against adult antigen Serologic detection of adult antigen Tracheal lavage or BAL Arteriogram
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Blood Chemistries and Urinalysis
Results of blood chemistries and urinalysis are usually normal. Although hyperglobulinemia does occur in some heartworm-infected cats, it is neither consistent nor predictable and should not be used to rule out FHD. Proteinurea has not been associated with FHD. 10 One cat with heartworms reportedly developed unilateral eosinophilic nephritis presumed to be associated with aberrant migration of larvaeY Microfilaria Detection
Experimental infections produced via L3 larvae or transplantation of adults usually result in a microfilaremia of short duration and low numbersP· 25 Concentration tests such as Knott tests or Millipore filter techniques are best. In North and South America, the only filarial disease of cats is heartworms; therefore, any microfilaria observed should be considered D. immitis. Serology
The confusion over the interpretation of the different tests and the variability of the methodology of individual laboratories has caused the practicing veterinarian problems in making a definitive diagnosis. With the high incidence of occult disease in the cat, the use of serology is a valuable asset. Three serologic methods have been used to assess FHD: 1. Immunofluorescence (IFA) for microfilarial antibody 2. Detection of host antibody against adult 3. Adult antigen detection by ELISA and colloid gold
Immunofluorescence Testing
Application of the canine IFA test (detecting antibodies to microfilarial cuticular antigen) was useful in early research and approximately diagnostic in about 33% of cats with adult heartworms,l 5 but the presence of immature or sterile worms, worms of only one sex, or the absence of host response to antigen does not produce a diagnostic titer. 15• 34 These assays have been helpful in researching the biology of the parasite-host interaction but have limited application to clinical diagnostics. Use of anti-D. immitis antibody to somatic antigens recently was reintroduced but has not been independently validated. Antibody Detection
The detection of feline antibodies to adult heartworm antigen has advantages over antigen testing in cats that demonstrate clinical signs
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consistent with FHD. Initial concerns related to false-positive results from cross-reactivity have not been observed. Initial studies of cats that have eliminated the adult parasite naturally or after adulticide reveals that a negative titer develops when the host antibody gradually decreases to negative concentrations (4 to 6 months). The antibody denotes a method of analysis; therefore, antigen preparation, antibody sources, and techniques can vary between diagnostic laboratories, and titers may differ accordingly. Because the antibody being detected is produced by the cat in response to the early migration of the L3 or L4 larvae, positive titers are detected about 2 to 3 months after a successful infection in about 50% of cats and is consistently positive by 5 months. 25, 26, 29, 34 Detection of antibodies in symptomatic cats does confirm a successful infection of the L3-L4 stages. However, with the use of macrolides as a preventative medication, the larvae in a cat can initiate a positive antibody response and then can be killed by the macrolide, leading to an antibody-positive but heartworm-negative outcome. Additionally, the death of adult heartworms may produce a strong antibody response after release of large amounts of antigen. 9 Some of the highest titers are associated with severe clinical signs in cats in which the worms have died and in which the disease may be resolving. 10 In rare cases, the antibody test result can be negative even in the presence of adult worms. Of the different antibody tests currently available, there are differences in the antibody that each appears to quantitate. There appears to be no correlation between antibody levels and the number of worms or severity of disease in the initial studies based on antibody titers by Animal Diagnostics Inc, St. Louis, Missouri. Detection of high concentrations of antibody to a specific heartworm antigen by Heska Co., Fort Collins, Colorado, has been noted in some cats with larger adult worm burdens. The author has observed confirmed cases of heartworms that are antibody negative by all current assays. Early evidence suggests that during an active heartworm infection, the currently available antibody detection methods are triggered by different antigens; thus, discordant results between two antibody testing methods should not surprise the veterinarian. Serial testing frequently yields a negative test that becomes positive 1 to 3 months later. Based on initial impressions, after an L3 larva infection, the polyclonal antibody detected by Animal Diagnostics is noted 1 to 2 months before the antibody detected by Heska Co. Although this indicates early infection, neither test result indicates adult infection. A positive antibody result shows that the cat has been successfully infected with L3larvae, that an L4 molt has occurred, and that the larvae have lived at least 2 to 3 months and may or may not have developed into adult heartworms. 25' 26 The duration of continued antibody response in a cat with a chronic adult infection (i.e., a cat with a 2-year-old heartworm) cannot be confirmed using all testing methods at this time. Because the antibody detection is specific for feline antibody, these methods cannot be used in other species.
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Antigen Testing
Heartworm antigen detection tests using blood or serum have been successful in dogs, and results have been positive in cats within days of transplantation of mature adult worms from dogs into cats. 10• 14 Because the majority of antigen being detected is derived primarily from the adult female reproductive tract, immature infections, a low worm burden, male-only infections, or sexually immature worms will not produce enough antigen to be detected. The elimination of the adult parasite also causes a negative antigen test. Early evidence suggests that new antigen detection methods may detect different antigens and may become positive before the typical 6- to 8-month interval after L3 larva infections. Cats may test positive for antigen 6 to 8 months after the experimental infections with large numbers of L3 larvae. 24-26 However, clinically infected cats and experimentally infected cats with active heartworm disease and high antibody titers can test negative for antigen. The low heartworm numbers in clinical infections and the clinical signs associated with immature worms make it prudent to consider a positive antigen test result diagnostic but not to rule out heartworms based on a negative antigen test result. Most cats with heartworm disease are antigen negative. Of the different assays for antigen in the blood, each should be reviewed for strengths and weaknesses. Data would support the basic consideration that a microwell titer technology on serum is best for detecting low antigen concentrations. Electrocardiography
Although subtle signs of right ventricular enlargement are occasionally noted (with unipolar chest leads) a right axis vector (>120°) on a standard six-lead EKG is rare. Ectopic ventricular beats and other arrhythmias have been observed infrequently after adulticide in asymptomatic cats. 10 Radiography
The pulmonary parenchymal changes are nonspecific and can change rapidly in infected cats. 9• 10• 20• 31- 33• 37 The lung lesions include diffuse or coalescing infiltrates, perivascular densities, and lung atelectasis. The most distinctive radiographic sign is enlarged pulmonary arteries with ill-defined margins, most prominent in the caudal lung lobes on the VD view (Fig. 4). Blunting and tortuosity of the pulmonary arteries are seen occasionally, but these findings are not as common in cats as in dogs. An enlarged main pulmonary arterial segment extending beyond the cardiac border on the VD or DV view is not a classic feature of feline heartworms. The enlargement of the caudal pulmonary artery may disappear over a period of several months. Some cats with heartworm disease have normal radiographic results. Severe infiltrative disease also may inhibit visualization of the pulmonary arteries. After an
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Figure 4. Enlargement of the right caudal pulmonary artery can be visualized beyond the edge of the cardiac shadow and is consistent with heartworm infections, but this lesion is not present in many cats with active adult infections.
acute episode, a lung lobe (left caudal, right caudal, or right middle) may appear consolidated (Fig. 5). The pulmonary interstitial edema and hemorrhage is often corticosteroid responsive? Atelectasis of the right middle lung lobe appears to be less likely to resolve and may become permanent. Arteriograms as a diagnostic tool may demonstrate the enlarged pulmonary arteries and embolus31 (Fig. 6). Nonselective angiocardiography is a simple and safe method of confirming a tentative diagnosis of heartworms. A radiographic exposure 5 to 6 seconds after injection of contrast material into the jugular vein will provide good visualization of the pulmonary vasculature and on occasion the presence of worms. There does not seem to be a correlation between the severity of lesions based on angiocardiographic results and the severity of clinical signs or postadulticide reaction. Because of the changing nature of the disease over time, repeated radiographs are often necessary. Echocardiogram
Parallel hyperechoic lines, representing an image from the heartworm cuticle, may be observed in the pulmonary arteries, right ventricle, or, rarely, the right atria. 6• 37• 39 • 40 These lines are generally not over 0.5 to
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Figure 5. Acute signs in this heart· worm cat was associated with acute lung injury of the left caudal lung lobe especially. The resultant pulmonary inflammation made identification of caudal pulmonary arteries difficult. Radiographic visu· alization of acute pulmonary lesions as in this radiograph may not be observed until 1 to 2 days after the acute crisis.
Figure 6. Nonselective angiogram is useful in identifying enlarged or occluded pulmonary arteries associated with heartworm disease. Cat heartworms can rarely be visualized.
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Figure 7. Gross examination demonstrates the nature of the acute pulmonary inflammation associated with this cat. One live female and 1 dead male heartworm was identified.
1 em in length because of the angle of the probe and curved nature of the worms in the heart. Heartworms in the most distal pulmonary arteries often cannot be visualized. Echocardiography is useful to confirm a tentative diagnosis of heartworms6• 39 (Fig. 7). The right parasternal view gives the best vantage point of the pulmonary outflow tract.39 The most common location of the adult worm is the pulmonary outflow tract. 6• 39 In the hands of an experienced individual, echocardiography in cats is diagnostic in over half the cases of FHD. Differential Diagnosis
In the cat with respiratory signs, heartworm disease must be differentiated from Aelurostrongylus abstrusus or Paragonimus kellicotti infection, asthma, cardiomyopathy, and other diseases associated with dyspnea (e.g., pyothorax, pleural effusions, pneumothorax, FIP, lymphosarcoma, and anemia)?· 10 Although each in various stages can mimic the clinical and radiographic pulmonary parenchymal changes, the pulmonary arterial changes of heartworm disease are unique, if present, and can be enhanced by contrast procedures. The changing clinical and radiographic pattern of disease make the diagnosis difficult, and over time there will be differences in diagnostic results. The peripheral eosinophilia, eosinophilic tracheal cytology, and chronic cough of feline heartworms is consistent with a diagnosis of "bronchial asthma." However, an apparent higher incidence of asthma has not been reported in heartworm-endemic areas. The enlarged pulmonary arteries and muscular hypertrophy of Aelurostrongylus abstrusus and Toxocara cati infection is clinically uncommon. CLINICAL MANAGEMENT OF FELINE HEARTWORM DISEASE
After the diagnosis of FHD, the veterinarian and client are in a lose-lose situation. Conservative management would be to hope that
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the adult worms die spontaneously over the next months to years and to endure the risk of continued chronic problems and/or an acutecrisis. The aggressive approach would include the use of an adulticide to eliminate the worms, risking the severe consequences of acute complications associated with the worm(s) dying at one time. Because of the dire consequences of management of FHD, preventative medication for cats is recommended if heartworm-infected dogs are in the area. Therapy for Heartworm-Positive Cats
Owners' attitudes dictate the approach. Because feline heartworminfected cats are often asymptomatic or demonstrate only chronic vomiting or intermittent respiratory signs, the owner must be reminded that this is a serious disease. Owners should be reminded that spontaneous acute complications and death do occur in a small percentage of cats with heartworms. No relationship has been detected between the clinical signs and risk of acute complications (Fig. 8). Because the adult heartworm has a shortened longevity in the cat as compared with the dog, the possibility of spontaneous recovery also should be discussed. The concept that heartworms do not live normal 5-year life spans in cats does not rule out the occasional cat that continues to have adult infections for 3 to 4
Figure 8. Echocardiogram demonstrating hyperechoic parallel lines (arrow) in right ventricle as the cuticle of a heartworm is visualized. The most common location is the right ventricle and main pulmonary arteries.
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years. Although, the natural death of the adult worms can be associated with severe respiratory signs, most cats recover without severe complications. Cats, managed conservatively by intermittent corticosteroid therapy, still are at risk for acute signs. In the cat with recurrent dyspnea that is life-threatening or with clinical signs that are unacceptable to the owner, adulticidal therapy has been used safely and should be considered. Adulticidal Therapy
Treatment of FHD with thiacetarsamide sodium (2.2 mg/kg intravenously twice daily for 2 days) is tolerated by cats without immediate complications of hepatotoxicity or renal toxicity. 10• 13 Concerns as to a direct acute lung injury from thiacetarsamide in normal cats causing pulmonary edema and respiratory failure 39 could not be reproduced in studies in 12 normal cats. 12 The use of ketamine as a sedative to aid in careful administration of thiacetarsamide is recommended in active cats. There are occasional reports of acute symptoms after thiacetarsamide injections, but slow injections have not caused acute collapse in normal healthy cats in this author's experience?· 8 Although the presence of circulating microfilaria is uncommon, ivermectin has been used successfully as a microfilaricide. Postadulticida/ Complications
Complications after therapy are usually related to acute lung injury associated with dying heartwormsY· 21 Sudden death from respiratory failure can occur, especially within the first 10 days after adulticide administration. Embolization can induce severe lung injury, hemoptysis, and dyspnea. Severe thrombocytopenia and disseminated intravascular coagulation have not been noted. Based on the assumption that heartworm mass is related to antigen load, a cat with a strongly positive antigen test result would be more likely to develop postadulticide complications. Worm death most often affects the caudal lung lobes, and thoracic radiographs may demonstrate a lung lobe with increased density. Oxygen therapy is indicated if dyspnea occurs. High doses of corticosteroids (1 to 2 mg/kg of prednisolone) with careful IV fluid therapy will often support the cat through the crisis. The routine use of corticosteroids is not recommended before or after thiacetarsamide in cats. Aspirin is not indicated in FHD. 31 • 32 Because of the potential protective effects of ketamine as a serotonin antagonist, a single intramuscular injection of ketamine has been recommended before administration of the first dose of thiacetarsamideP The acute nature of the postadulticide reaction dictates that the cat be under 24-h/ day observation, especially during the first 2 weeks. The clinical and radiographic signs of acute embolization can resolve over 1 to 2 days. However, death can occur before therapy can be instituted. The client should be aware that the risk of complications in the cat seems to be greater than in the dog. The
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severity of the postadulticidal reaction poses a dilemma for the veterinarian, and the risk of postadulticide complications is probably greater than the risk of spontaneous death in the asymptomatic, heartworminfected cat. The advantage of treating a cat is being able to observe the cat during the 2-week period after thiacetarsamide therapy while the worms are dying, compared with waiting for the spontaneous death of worms. However, adulticidal therapy in one study did not increase the mean survival time in cats administered an adulticide compared with those treated conservatively. 1 Owners should be advised that 30% of cats receiving adulticidal therapy will have a life-threatening crisis within 3 weeks of therapy_?, 10 Efficacy of Treatment
The efficacy of thiacetarsamide cannot be evaluated in many client cats because of the occult nature of the disease. However, current research seems to indicate that the adulticide is effective and clinical signs usually abate during the initial weeks after thiacetarsamide, 30 Based on data from studies on dogs, immature worms are probably resistant to thiacetarsamide. If a cat was antigen positive before therapy, the antigen test result should be negative 12 weeks after successful adulticide therapy. Data on imiticide use in FHD is limited, but antidotal reports would advise against using the dog protocol. Surgical Therapy
Removal of heartworms via jugular venotomy has been used successfully with an endoscopic basket3 and by wrapping the heartworms with horsehair brushes or Swan-Ganz balloon flotation catheters. More invasive is a thoracotomy and removal of the heartworms by right ventricular incision or pulmonary arteriotomy. Invasive surgery should be reserved for cats with heartworms that have been visualized by echocardiography. Conservative Therapy
The owner should be educated as to the nature of the peracute signs of heartworm disease. Alternate day prednisolone therapy (2 to 5 mg/ kg) has been used successfully to prevent clinical signs of coughing and vomiting. However, progression of radiographic lesions has been observed during corticosteroid therapy. In addition, acute respiratory distress and death have occurred in cats on conservative glucocorticoid therapy. An emergency dose of oral or injectable glucocorticoid should be dispensed to the owner to be administered if collapse or dyspnea are noted. The onset of acute respiratory signs in a heartworm cat is a true emergency requiring immediate care. The radiographic signs of severe lung pathology should not be overinterpreted as "consolidation or pneumonia." The initiation of intranasal oxygen therapy, cage rest, small
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volumes of intravenous fluids, and injectable prednisolone (100 to 250 mg prednisolone sodium succinate IV) has resulted in clinical improvement and resolution of radiographic signs within 24 hours of presentation in cats with life-threatening dyspnea and collapse. Subtle respiratory signs should be treated aggressively in heartworm-positive cats. Serial antibody testing (6-month intervals) can be used to assess the heartworm status. Generally, cats that have eliminated the adult infection will be antibody negative 6 to 9 months after all adults worms have been removed (Fig. 9). Preventative Medication
In endemic areas with vector populations (dogs) providing the mosquito with a reservoir, the incidence of heartworms in cats and the dire consequences of the infection indicate that preventive medication is warranted. Studies in most endemic areas indicate an infection rate, based on necropsy data, of 2.5% to 16%, with a median of 7%.34• 35 The antibody test reflects successful infection of L3 larvae, molting to L4 larvae, and survival for at least 2 to 3 months. Of 215 cats presented to 15 practices in the southeastern United States with vomiting or respiratory signs, 43% were antibody positive, and 11% lived indoors 100% of the time and 35% lived outdoors less than 90% of the time.33 In this
Figure 9. Chronic lesions associated with cats after heartworm disease can be collapse of a lung lobe that does not reinflate (right middle in radiograph) and peribronchial densities. This cat had been antigen- and antibody-negative for 2 years, and corticosteroid medication on an alternate day dosing was required to prevent coughing and occasional dyspneic episodes.
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author's experience and in a study at North Carolina State University/ one third of cats with FHD are considered indoor cats by their owners. Ivermectin (24 J,Lg/kg) 23 and milbemycin (500 J.Lg/kg)3 8 administered per os once a month safely prevent heartworm infections in cats. Heartgard for Cats, (24 J.Lg/kg ivermectin; Merial Limited, Iselin, NJ) has received US Food and Drug Administration approval for use in cats. In endemic areas, it is suggested that preventative medication be administered at 4 to 6 weeks of age and continued for the life of the cat. Although heartworm disease may be of low incidence in many areas, the high rate of complications associated with FHD makes preventative medication an attractive alternative. Because current antigen testing is inconsistent in cats, especially those with a low worm burden, antigen testing before instituting preventative therapy in an adult cat would not seem to be cost effective. Antibody testing would be positive if the cat had been successfully infected and the heartworm had lived at least 2 to 3 months but does not equate with status of adult infections. Furthermore, a heartwormpositive cat even with microfilaria can be safely administered Heartgard for Cats. 23 Regardless of any of the serodiagnostic results, a cat can be safely placed on preventative medication. The diagnostics would aid the owner and veterinarian in knowing the risk of infection in the cat. If either antigen or antibody positive, additional diagnostics could be pursued. The status of diagnostics before preventative medication will continue fo evolve as diagnostic modalities become more refined. After a cat has been on preventative medication, if exposed to L3 larvae, the larvae may live long enough to induce a positive antibody response in the cat but would not develop an adult infection. The antibody test would have limited application in yearly rechecks of cats unless in the future antibody levels can be used to distinguish between precardiac infections and adult infections. Although heartworm disease can be self-limiting in many cats, the potential to initiate inflammatory lung disease and predispose to bronchial asthma may prove to be adequate indications for preventative medications for cats in endemic areas. References 1. Atkins CE, DeFrancesco TD, Miller M, et al: Prevalence of heartworm infection in cats cardiorespiratory abnormalities [Abstract]. J Vet Med 10:161, 1996 2. Benard MA: Acute dirofilarial death. Can Vet J 11:190-191, 1978 3. Borgarelli M, Venco L, Piga PM, Bonino F, Ryan WG: Surgical removal of heartworms from the right atrium of a cat. J Am Vet Med Assoc 211:68, 1997 4. Calvert CA, Mandell CP: Diagnosis and management of feline heartworm disease. J Am Vet Med Assoc 180:565, 1982 5. Cusick PK, Todd KS, Blake JA, et al: D. immitis in the brain and heart of a cat from Massachusetts. J Am Anim Hosp Assoc 12:490, 1976 6. DeFrancesco TD, Atkins CE, Meurs K: Diagnostic utility of echocardiography in heartworm disease [Abstract]. J Vet Intern 11:141, 1997
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7. Dillon AR: Feline heartworms: More than just a curiosity. Vet Forum Dec:18, 1995 8. Dillon AR, Warner AE, Molina R: Dirofilaria immitis infection in dogs and cats results in pulmonary airway epithelial and microvascular injury. J Vet Intern Med 7:119, 1993 9. Dillon AR, Brawner WR, Grieve RB, et al: The chronic effects of experimental Dirofilaria immitis infection in cats. Vet Med Surg 2:72, 1987 10. Dillon AR: Feline heartworm disease. In Fox, Sisson (eds). Canine and Feline Cardiology. Philadelphia, WB Saunders, in press 11. Dillon AR, Warner AE, Molina RM, Soli MD, Knight DH: Pulmonary parenchymal changes in dogs and cats after experimental transplantation of dead Dirofilaria immitis. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April2. Batavia, IL, American Heartworm Society, 1995, pp 97-101 12. Dillon R, Cox N, Brawner B, D'Andrea G: The effects of Thiacetarsamide administration to normal cats. In Soli MD (ed): American Heartworm Society Proceedings. Batavia, IL, American Heartworm Society, 1994, pp 133-137 13. Dillon AR: Feline dirofilariasis. In Atwell, Bareham (eds): Dirofilariasis. Queensland, Australia, CRC Press, 1988, 205-215 14. Dillon AR: Feline heartworm disease. Vet Clin North Am 14:1185, 1984 15. Dillon AR, Sakas PS, Buxton BA, et al: Indirect immunofluorescence testing for diagnosis of occult Dirofilaria immitis infection in three cats. JAm Vet Med Assoc 180:80, 1982 16. Donahoe JM, Holzinger EA: D. immitis in the brains of a dog and a cat. J Am Vet Med Assoc 164:518, 1974 17. Donahoe JR, Kneller SK, Lewis RE: Hematologic and radiographic changes in cats after inoculation with infective larvae of D. immitis. JAm Vet Med Assoc 168:413, 1976 18. Fowler JL, Matsuda K, Fernan RC: Experimental infection of the domestic cat with D immitis. JAm Vet Med Assoc 19:79, 1972 19. Genchi C, Di Sacco B, Cancrini G: Epizootiology of canine and feline heartworm infections in Northern Italy: Possible mosquito vectors. In Soli MD (ed): American Heartworm Society Proceedings. Batavia, IL, American Heartworm Society, 1994, pp 39-46 20. Holmes RA, Clark JN, Casey HW, et al: Histopathologic and radiographic studies of the development of heartworm pulmonary vascular disease in experimentally infected cats. In Soli MD (ed): Proceedings of the Heartworm Symposium '92. Batavia, IL, American Heartworm Society, 1992, pp 81-89 21. Holmes RA. Feline heartworm disease. Compend Cantin Educ Pract Vet 15:687, 1993 22. Kobayashi Y, Awakura T, Shimada A, Umemura T, Yao M, Sato H. Dirofilariasis in a cat with eosinophilic interstitial nephritis. J Jpn Vet Med Assoc 45:862, 1992 23. Longhoffer SL, Dauria CP, Plue RE, Alva R, Wallace DH, Roncalli RA. Ivermectin for prevention of feline heartworm disease. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 177-182 24. Mansour AE, McCall JW, McTier TL, Supakorndej N, Ricketts R, Soli MD, Knight DH: Epidemiology of feline dirofilariasis. Infections induced by simulated natural exposure to Aedes aegypti experimentally infected with heartworms. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 87-95 25. McCall JW, Nonglak S, Ryan W, Soil MD: Utility of an ELISA-based antibody test for detection of heartworm infection in cats. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 127-133 26. McTier TL, Supakorndej N, McCall JW, Dzimianski MT: Evaluation of ELISA-based adult heartworm antigen test kits. In Soli MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, Auburn, Alabama, March 31-April 2. Batavia, IL, American Heartworm Society, 1995 27. Otto GF: Abnormal host = abnormal locations. Am Heartworm Soc Bull4:14, 1978 28. Padrid P, Feldman BF, Funk K, Samitz EM, Rei! D, Cross CE: Cytologic, microbiologic, and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 healthy cats. Am J Vet Res 52:1300, 1991
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29. Prieto C Venco L, Simon F, Genchi C: Feline heartworm (Dirofilaria immitis) infection: Detection of specific IgG for the diagnosis of occult infections. Vet Parasitol 70:209, 1997 30. Rawlings CA: Heartworm Disease in Dogs and Cats. Philadelphia, WB Saunders, 1986, pp 329 31. Rawlings CA: Pulmonary arterography and hemodynamics during feline heartworm disease. J Vet Intern Med 4:285, 1990 32. Rawlings CA: Pulmonary arteriography and hemodynamics during feline heartworm disease. J Vet Intern Med 4:285, 1990 33. Robertson C Dillon AR, Brawner W: Clinical study of 215 cats in South Eastern US Practices. Am Assoc Vet Parasitol ??:81, 1997 34. Ryan WG, Gross SJ, Soil MD. Diagnosis of feline heartworm infection. In Soll MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 121-126 35. Ryan WG, Newcomb KM. Prevalence of feline heartworm disease-A global review. In Soll MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 79-86 36. Schafer M, Berry CR. Cardiac and pulmonary artery mensuration in feline heartworm disease. Vet Radio! Ultrasound 36:499, 1995 37. Selcer BA, Newell SM, Mansour MS, McCall JW. Radiographic and 2-D echocardiographic findings in eighteen cats experimentally exposed to D. immitis via mosquito bites. Vet Radio! Ultrasound 37:3744, 1996 38. Stewart VA, Blagburn BL, Hendrix CM, Hepler DI, Grieve RB. Milbemycin oxime as an effective preventative of heartworm (Dirofilaria immitis) infection in cats. In Soll MD, Knight DH (eds): Proceedings of the Heartworm Symposium '95, March 31-April 2. Batavia, IL, American Heartworm Society, 1996, pp 126-131 39. Turner JL, Lees GE, Brown SA, Knauer KW, Yager LM, Edwards JF, Reagor JC: Thiacetarsamide in healthy cats: Clinical and pathological observations. J Am Anim Hosp Assoc 27:275, 1991 40. Venco L, Ghelfi E, Calzolari D, Morini S: Diagnostic techniques (radiography, electrocardiography, ultrasound) in heartworm disease in cats. Vet Cremona 10:23, 1996 41. Wong MM, Pedersen NC, Cullen J: Dirofilariasis in cats. J Am Anim Hosp Assoc 19:855, 1983 42. Zeidner NS, Belasco DL, Dreitz MJ, Frank GR, Usinger WR. Gliding bacterial adjuvant stimulates feline cytokines in vitro and antigen-specific IgG in vivo. Vaccine 13:1294, 1995
Address reprint requests to: Ray Dillon, DVM, MS Department of Small Animal Medicine and Surgery College of Veterinary Medicine Auburn University Auburn, AL 36849