Dirofilaria immitis in Cats: Diagnosis and Management *

CE Article #2 Dirofilaria immitis in Cats: Diagnosis and Management * C. Thomas Nelson, DVM a Animal Medical Centers of Northeast Alabama Anniston, Alabama ABSTRACT: Imaging and laboratory studies can help with the diagnosis of heartworm disease in cats, but no test is definitive. Furthermore, even when the diagnosis can be reliably established, therapy directed at the heartworms does little to help the cat. Rather, management is directed at alleviating clinical signs, with an emphasis on prevention for all. Take CE tests See full-text articles CompendiumVet.com Diagnosis is the most challenging part of feline heartworm disease because no single test can reliably detect heartworms at all stages. Veterinarians must be willing to conduct multiple and even repeat tests (Table 1 and Figure 1) to obtain a diagnosis and to correctly interpret and apply the results. b *A companion article on prevalence and pathophysiology begins on page 382. a Dr. Nelson discloses that he has received financial support from the American Heartworm Society, the Companion Animal Parasite Council, IDEXX Laboratories, Fort Dodge Animal Health, the KNOW Heartworms campaign, Merial, and Pfizer Animal Health. b For the complete American Heartworm Society 2007 Guidelines for the Diagnosis, Prevention and Management of Heartworm (Dirofilaria immitis) Infection in Cats, please visit www.heart wormsociety. org. DIAGNOSIS Microfilariae Filtration tests for microfilariae are virtually useless in cats because cats are only transiently microfilaremic, if at all. To be microfilaremic, a cat must have both a mature male and a mature female worm, and because cats typically only have one or two worms, the infections are often single sex. When microfilariae are produced, they are only present for 1 or 2 months, at which time the cat s immune system eliminates them and suppresses further embryogenesis. 1 Radiology The most common radiographic finding in feline heartworm disease is an enlargement of the right caudal lobar artery (see Figure 2 in the companion article beginning on page 382). This is best seen on a ventrodorsal view. A bronchointerstitial pulmonary pattern (Figure 2) may also be noted, but this finding is not unique to feline heartworm disease. The use of radiology has limitations, as only 55% of heartworm antigen positive cats had radiographic signs consistent with heartworm disease in one study. 2 Follow-up on some of these cats showed improvement in radiographic scores in 50% of cases and worsened scores in 16%. Because cats can tolerate adult worm infections fairly well and it is common for clinical signs to either resolve or become intermittent, such results are to be expected. Echocardiography In skillful hands, ultrasonography has been shown to detect 100% of adult feline heart- July 2008 393 COMPENDIUM

394 CE Dirofilaria immitis in Cats: Diagnosis and Management Table 1. Interpretation of Heartworm Diagnostic Tests in Cats Test Purpose Result and Interpretation Limitations Antibody test Detects antibodies produced in response to late L4, juvenile, and adult worms. May detect infections as early as 8 weeks posttransmission Negative Decreases index of suspicion Positive Increases index of suspicion; confirms cat is at risk Antibodies confirm recent infection to at least late L4 stage but do not confirm disease causality Antigen test Detects antigen from an adult female heartworm, >5 dying male heartworms, or a dying female heartworm Negative Decreases index of suspicion Positive Confirms presence of heartworms Immature or maleonly worm infections are rarely detected Thoracic radiography Detects vascular enlargement (inflammation and hypertrophy caused by a juvenile worm), pulmonary parenchymal inflammation, and (more rarely) edema Normal Decreases index of suspicion Signs consistent with feline heartworm disease Enlarged arteries greatly increase index of suspicion Radiographic signs are subjective and affected by clinical interpretation Echocardiography Detects echogenic walls of the immature or mature heartworm residing in the lumen of the pulmonary arterial tree (only within the visual ultrasonographic window) No worms seen No change in index of suspicion Worms seen Confirms presence of heartworms in the structure Accuracy depends in part on the ultrasonographer s experience with heartworm detection American Heartworm Society worm infections, but the technician must be able to follow the caudal pulmonary arteries to their bifurcation within the lung fields. 3 Other reports cite echocardiography as detecting 68% of natural infections 4 and 88% of experimental infections in cats. 5 The cuticle of the adult heartworm is strongly echogenic, producing short, segmented, parallel lines where the imaging plane crosses the worm. Heartworm signatures on echocardiography have been described as equal signs (=; Figure 3). However, the imaging beam may cross the same worm multiple times, making quantifying the number of worms difficult. Serology There is an ongoing debate about the accuracy of antigen and antibody testing for feline heartworm disease. Both tests can provide valuable information, but a thorough understanding of their limitations is essential to interpreting results correctly. Antigen tests are considered the gold standard in diagnosing heartworms in dogs. However, they do not detect early or male-only worm infections. Part of the disease process in cats is the death of juvenile worms at 3 to 4 months postinfection, which antigen tests cannot detect. Again, because most infected cats have one or, at most, two adult worms, single-sex, male-only infections are common. 1 Multiple studies have reported the sensitivity of antigen testing in mature heartworm infections in cats to be 50% to 86%. 6 9 As a result, a negative antigen test result does not rule out heartworm infection in cats. The antibody test was initially very promising. In experimental studies, it detected 93% to 100% of heartworm infections, including late L4 larvae as well as juvenile and adult worms. 7,10,11 However, a significant number of cats with adult heartworms are antibody negative. For example, in a retrospective study of 50 cats with known heartworm disease, there was a 14% falsenegative rate. 12 Most of the cats in the study (72%) had clinical signs indicating active disease. A necropsy study of shelter cats in Texas 6 reported a 50% false-negative rate for one antibody test, and a similar study in Florida had an 11% to 68% false-negative COMPENDIUM July 2008

CE 395 rate on eight different antibody tests. 8 Twenty-one of 31 cats with heartworm disease had a negative result on at least one of the eight antibody tests evaluated. All of these studies have drawbacks, but collectively they demonstrate that a negative antibody test result cannot be used to rule out heartworm infection. The use of antigen and antibody tests must be tempered by an awareness of these limitations. It is difficult to establish a diagnosis with a single method unless the antigen test result is positive or a worm is detected on ultrasonography. Diagnosis generally requires multiple tests. If antibody or antigen testing is used for initial screening, the practitioner should be prepared to conduct additional tests if the results do not support the clinical suspicions. This is illustrated by the results of a study of 22 heartworm-infected cats in which thoracic radiography, echocardiography, and antigen and antibody tests were conducted. Pulmonary enlargement was seen in 64% of the cats, worms were visualized by echocardiography in 64%, 55% were antigen positive, and 82% were antibody positive. 13 In a multicenter study of 215 cats in which clinical signs were correlated to serology and radiographic findings, 44% of the cats that presented with coughing or dyspnea and intermittent vomiting unrelated to eating were antibody positive. 14 This was twice the antibody base rate for the area. Of the cats with radiographic signs consistent with heartworm disease, 60% were antibody positive. IMPLICATIONS Because heartworm disease in cats is primarily caused by juvenile worms, antibody serology data can be used to estimate the percentage of cats infected at some point in their life span, thus establishing regional risk. In 1997, 15.9% of the 25,277 cats tested at Heska s reference laboratory were antibody positive. 15 A second study mainly conducted in the Northeastern and Midwestern states reported a 12% antibody-positive rate. 16 Analysis of data from IDEXX reference laboratories shows the national rates of feline heartworm antigen, FeLV, and FIV detection to be 1%, 1.9%, and 1%, respectively, indicating that heartworm disease is a significant health risk in cats. 17 As a result, IDEXX is adding a heartworm antigen spot to its point-of-care test for FeLV and FIV. This new format should increase the number of cats tested yearly for heartworms from tens of thousands to millions. It is important for practitioners to understand that they will be testing for the presence of the adult female worm. Although all cats with adult worms have heartworm- July 2008 COMPENDIUM

396 CE Dirofilaria immitis in Cats: Diagnosis and Management Antibody Test or Radiography Positive result increases index of suspicion Negative result lowers index of suspicion positive rate is 16%, 50% of cats with known HARD lesions (including 25% to 30% of cats with adult heartworms 6,8 ) are antibody negative 8 months after infection. 18 Based on these numbers, it could be argued that the percentage of cats at risk for HARD in a given area is twice the base antibody rate (32%). At the same time, Browne et al 19 have showed that half of antibody-positive cats (50% of 16% = 8%) have lung lesions consistent with HARD. If, at a conservative estimate, an additional 2% of cats that are negative on all tests have HARD, there may be as many as 10 cats with HARD for every one cat identified as having adult heartworms. Given that the adult heartworm infection rate in cats is 10% of the rate in unprotected dogs and that for every cat with an adult infection there may be 10 cats with HARD from juvenile infections, it is possible that cats are infected at the same rate as dogs. Antigen Test or Echocardiography Positive result is diagnostic Negative result lowers index of suspicion Figure 1. Summary of interpretation of heartworm diagnostic tests in cats. associated respiratory disease (HARD), not all cats with HARD have adult worms. The clinical signs associated with most cases of HARD are the result of juvenile worm infections and are not detected by antigen testing. Nonetheless, it is likely that, in the first year of the new test s availability, more than 25,000 cats will be diagnosed with adult heartworm infections that previously would not have been detected. What are the implications of increased testing? In addition to the rude awakening in store for veterinarians and cat owners who did not believe heartworms Treatment is also difficult because no form of medical adulticidal therapy has been shown to increase the survival rate of cats harboring adult heartworms. existed in cats in their area, it should provide more information about cats at risk for HARD. The 1% heartworm antigen positive rate will probably emerge as just the tip of the iceberg (Figure 4) of cats with or at risk for HARD because only cats with adult female heartworms test positive for antigen. Also, a significant number of cats infected with heartworms at any stage are missed due to the limitations of current testing modalities. Although the nationwide antibody- TREATMENT Because no form of medical adulticidal therapy has been shown to increase the survival rate of cats harboring adult heartworms, treatment is aimed at controlling clinical signs. On diagnosis, thoracic radiographs should be obtained or reviewed to look for any evidence of vascular, bronchointerstitial, or parenchymal disease. Cats exhibiting clinical or radiographic signs of disease should be given antiinflammatory doses of glucocorticosteroids (prednisone, 1 to 2 mg/kg/day), reduced weekly over a 3- to 4-week period. If clinical signs recur or persist, alternate-day glucocorticosteroids should be given at the lowest effective dose. Radiography and serology are then repeated every 6 months to monitor the course of the disease. A monthly heartworm preven- COMPENDIUM July 2008

CE 397 Figure 2. Radiographic evidence of heartworm infection. Bronchointerstitial pattern. Figure 3. Heartworm signatures of echocardiography (arrows). (Image courtesy of Clarke Atkins, DVM, DACVIM [Internal Medicine and Cardiology], North Carolina State University) tion regimen should be initiated for all cats; because microfilaremia is typically rare or marginal in cats (unlike dogs), it is safe to administer preventive agents to heartworm-positive cats. Cats presenting in acute respiratory distress should be given oxygen, shock doses of glucocorticosteroids (dexamethasone sodium phosphate, 1 to 2 mg/kg IM or IV, or prednisolone sodium succinate, 50 to 100 mg/kg/cat IV), and a bronchodilator (e.g., aminophylline, 6.6 mg/kg IV). Supportive therapy (IV fluids and thermal support) is maintained until the cat s condition is stabilized. Retrospective studies indicate that 10% to 20% of cats with adult heartworm infections die as a result of complications from a dead or dying heartworm. 20 Owners of cats July 2008 COMPENDIUM

398 CE Dirofilaria immitis in Cats: Diagnosis and Management 1% HARD 8%+2%=10% 16% Ab+ 32% of cats at risk Nationwide heartworm antigen positive rate. 17 Of the 16% of cats that are Ab+ without adult worms, half, or 8%, have pulmonary parenchymal lesions (HARD). 19 Nationwide heartworm antibody positive rate. 15 The 16% Ab+ rate may represent only half of the cats at risk for HARD. In one study, 50% of cats with known HARD lesions were Ab within 8 months after infection. 19 Figure 4. Heartworm antigen and antibody test results versus potential numbers of cats at risk for HARD. According to the study conducted at Heska s reference laboratory, 15 the nationwide heartworm antibody positive (Ab+) rate in cats is approximately 16%. Browne et al 19 have showed that half of Ab+ cats have lung lesions consistent with HARD; therefore, it is possible that, nationwide, 8% of cats have HARD. If 50% of cats with known HARD lesions (including 25% to 30% of cats with adult heartworms 6,8 ) are antibody negative (Ab ) 8 months after infection, 18 it is possible that the 16% Ab+ rate represents only half of the cats at risk for HARD, for a total of 32% of cats potentially at risk. If, at a conservative estimate, an additional 2% of these Ab cats have HARD, as many as 10% of cats may have HARD from juvenile infections.this makes the 1% antigen-positive rate 17 merely the tip of the iceberg. before administering adulticidal medication reduces the pathology associated with worm death, 24 but similar studies have not yet been completed in cats. PREVENTION All indoor and outdoor cats in endemic areas should receive heartworm prevention because the risk for indoor cats has been shown to be similar to that for outdoor cats. 12,14,16 There are four products on the market labeled for cats that are safe and virtually 100% effective in preventing heartworm infection. Ivermectin is available as a chewable treat, milbemycin as a flavored tablet, Heartworm disease in cats can be difficult to diagnose because no single test can detect heartworms at all stages. with an adult heartworm infection diagnosed either by antigen testing or echocardiography should be informed about this risk and instructed to seek prompt medical attention at any sign of respiratory distress. It may be prudent to give the owner a syringe containing 10 mg of dexamethasone sodium phosphate with instructions to administer in the event of a respiratory crisis to initiate treatment, but it must be emphasized that this does not eliminate the need for emergency veterinary care. There is anecdotal evidence that antileukotrienes (e.g., montelukast, 2 mg/day) may help to thwart an acute, fatal lung injury when an adult worm dies. Dillon 21 has been using this approach for more than 6 years, and no cat so treated has yet presented in acute respiratory distress. There is also interest in the use of doxycycline in heartworm-positive cats. Heartworms harbor an intracellular endosymbiont of the genus Wolbachia, which is found in many of the filarial nematodes that cause disease in humans and animals (including Onchocerca volvulus, Wuchereria bancrofti, Brugia malayi, and Dirofilaria immitis). Doxycycline is now being used to treat some filarial nematode infections in humans. 22,23 Studies indicate that pretreating a dog with doxycycline and selamectin and moxidectin as topical applications. Spectra vary among products, but all control multiple parasites in addition to heartworms. CONCLUSION Although the promise of universal heartworm antigen testing in cats will not translate into universal detection, the concept of monthly prevention in all cats should be readily understandable to owners. With veterinarians leading the way in public education, preventive measures for cats may soon be as acceptable as they currently are for dogs. COMPENDIUM July 2008

CE 399 REFERENCES 1. McCall JW, Dzimianski MT, McTier TL, et al. Biology of experimental heartworm infection in cats. In: Soll MD, ed. Proceedings of the Heartworm Symposium 92. Batavia, IL: American Heartworm Society; 1992:71-79. 2. Brawner WR, Dillon AR, Robertson-Plough CK, Guerrero J. Radiographic diagnosis of feline heartworm disease and correlation to other clinical criteria: results of a multicenter clinical case study. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:91-95. 3. Venco L, Morini S, Ferrari E, Genchi C. Technique for identifying heartworms in cats by 2-D echocardiography. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:97-102. 4. Defrancesco TC, Atkins CE. The utility of echocardiography in the diagnosis of feline heartworm disease: a review of published reports. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:103-105. 5. Atkins CE, Arther RG, Ciszewski DK, et al. Echocardiographic quantification of Dirofilaria immitis in experimentally-infected cats. Vet Parasitol 2008. Accepted for publication. 6. Nelson CT, Self TS. Incidence of Dirofilaria immitis in shelter cats in southeast Texas. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society, 1998:63-66. 7. McCall JW, Guerrero J, Supakorndej P, et al. Evaluation of the accuracy of heartworm antigen and antibody test for cats. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:127-134. 8. Snyder PS, Levy JK, Salute ME, et al. Performance of serologic tests used to detect heartworm infection in cats. JAVMA 2000;216:693-700. 9. Berdoulay P, Levy JK, Snyder PS, et al. Comparison of serological tests for the detection of natural heartworm infection in cats. JAAHA 2004;40:376-384. 10. Bestul KJ, McCall JW, Nonglak S, et al. Evaluation of the Assure FH antibody assay for the detection of feline heartworm infection. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:179-186. 11. Donoghue AR, Mondesire RR, Porter JP. Detection of antibodies to Dirofilaria immitis in the cat using a highly specific recombinant antigen. Presented at the North American Veterinary Conference, Orlando, FL, January 11-15, 1997. 12. Atkins CE, DeFrancesco TC, Coats JR, et al. Heartworm infection in cats: 50 cases (1985-1997). JAVMA 2000;217:355-358. 13. DeFrancesco TC, Atkins CE, Miller MW, et al. Use of echocardiography for the diagnosis of heartworm disease in cats: 43 cases (1985-1997) JAVMA 2001;218(1):66-69. 14. Dillon AR, Brawner WR, Robertson-Plough CK, Guerrero J. Feline heartworm disease: correlation of clinical signs, serology, and other diagnostics. Results of a multicenter study. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:153-158. 15. Piche CA, Cavanaugh MT, Donoghue AR, Radecki SV. Results of antibody and antigen testing for feline heartworm infection at Heska veterinary diagnostic laboratories. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:139-143. 16. Miller MW, Atkins CE, Stemme K, et al. Prevalence of exposure to Dirofilaria immitis in multiple areas of the United States. In: Seward RL, ed. Recent Advances in Heartworm Disease: Symposium 98. Batavia, IL: American Heartworm Society; 1998:161-166. 17. Lorentzen L, Caoloa A. Incidence of positive heartworm antibody and antigen tests at IDEXX Laboratories: trends and potential impact on feline heartworm awareness and prevention. Vet Parasitol 2008. Accepted for publication. July 2008 COMPENDIUM

400 CE Dirofilaria immitis in Cats: Diagnosis and Management 18. Dillon AR, Blagburn BL, Tilson DM, et al. Immature heartworm infection produces pulmonary parenchymal, airway, and vascular disease in cats. Presented at the 12th Triennial Heartworm Symposium, Washington, DC, July 2007. 19. Browne LE, Carter TD, Levy JK, et al. Pulmonary arterial disease in cats seropositive for Dirofilaria immitis but lacking adult heartworms in the heart and lungs. Am J Vet Res 2005;66:1544-1549. 20. Genchi C, Venco L, Ferrari N, et al. Feline heartworm (Dirofilaria immitis) infection: a statistical elaboration of the duration of the infection and life expectancy in asymptomatic cats. Vet Parasitol 2008. Accepted for publication. 21. Heartworm-Associated Respiratory Disease in Cats. Pfizer Animal Health; 2007. Accessed May 2008 at http://www.advanstarvhc.com/c9. 22. Hoerauf A, Mand S, Adjei O, et al. Depletion of Wolbachia in Onchocerca volvulus by doxycycline and microfilaridermia after ivermectin treatment. Lancet 2001;357:1415-1416. 23. Taylor MJ, Bandi C, Hoerauf AM, Lazdins J. Wolbachia bacteria of filarial nematodes: a target for control? Parasitol Today 2000;16:179-180. 24. McCall JW, Genchi C, Kramer L, et al. Heartworm and Wolbachia: therapeutic implications. Vet Parasitol 2008. Accepted for publication. ARTICLE #2 CE TEST This article qualifies for 2 contact hours of continuing CE education credit from the Auburn University College of Veterinary Medicine. Subscribers may take individual CE tests or sign up for our annual CE program. Those who wish to apply this credit to fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program. CE subscribers can take CE tests online and get real-time scores at CompendiumVet.com. 1. Because heartworm infection in cats typically involves only one or two juvenile worms, it rarely causes a. pulmonary symptoms. b. a host reaction. c. microfilaremia. d. vascular inflammation. 2. Radiographic signs of heartworm infection in cats a. are present in only about 55% of cases. b. generally improve in about 50% of cats that have them. c. often appear as an enlargement of the right caudal lobar artery. d. all of the above 3. The echocardiographic signature of feline heartworm disease consists of a. an equal (=) sign. b. a wavy (~) sign. c. av sign. d. a C sign. 4. Antigen testing has limited value in cats because a. it primarily detects only mature, female worms. b. cats seldom have an immune reaction to the presence of worms. c. it has a low sensitivity in both cats and dogs. d. it is effective only in the microfilaremic stage. 5. Antibody testing cannot be used to rule out heartworm infection in cats because a. it cannot detect all stages of the worm s life cycle. b. it has a high false-negative rate. c. frequent false-positive results can lead to overtreatment. d. all of the above 6. When diagnostic tests were compared in the same group of infected cats, heartworm infection was most consistently detected by a. thoracic radiography. b. echocardiography. c. antibody testing. d. antigen testing. 7. Data from a group of reference laboratories show similar infection rates for feline heartworm disease and a. FeLV. b. feline infectious peritonitis. c. FIV. d. Lyme disease. 8. The primary advantage of increased antigen testing is the identification of cats a. that need adulticidal therapy. b. that should be quarantined. c. with compromised immunity. d. at risk for HARD. 9. The mainstay of symptomatic therapy for cats with heartworm disease is a. glucocorticosteroids. b. bronchodilators. c. NSAIDs. d. parasiticidal agents. 10. A heartworm disease prevention regimen should be initiated a. only in cats found to be antigen negative on two consecutive tests. b. only in cats younger than 6 months. c. in all cats that show no signs of HARD. d. in all cats, regardless of infection status. COMPENDIUM July 2008