Dirofilaria immitis

Authors: Rajeev Bais M.D, Helmut Albrecht, M.D.

Previous Authors (2nd Edition, 2002): Helmut Albrecht, M.D., Robin Hampton M.D., Ph.D.

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PARASITOLOGY

Human dirofilariasis is a zoonosis caused by animal filarial parasites including Dirofilaria immitis, D. (Nochtiella) repens, D. tenuis and several other less common Dirofilaria and Nochtiella species. As with the human filarial counterparts (Brugia, Wucheria), Dirofilaria are transmitted by an arthropod intermediate host. Except for D. ursi, which is transmitted by blackflies (Simulium species), dirofilaria are transmitted by various mosquitos species including Aedes, Anopheles, and Culex species, in which the microfilariae develop for about two weeks before reaching the infective stage L3. Dogs, wild canids (such as wolves and foxes), raccoons ( D. tenuis), and other mammals comprise the definitive host reservoir. After developing in subcutaneous tissues of the host animals dirofilaria enter the blood supply and mature in the right side of the heart and pulmonary arteries resulting in heart failure and pulmonary complications, explaining the lay labeling of dirofilaria as "heartworm" (16). Humans are accidental hosts and human infection does not progress to allow for development into sexually mature helminths.

EPIDEMIOLOGY

In the United States canine infections were previously confined to the southeastern states but with the expansion of disease carrying mosquito vectors now have a much more widespread distribution. The highest infection rates are still found within 150 miles of the coast from Texas to New Jersey, and along the Mississippi River and its major tributaries but transmission of the parasite now occurs in all of North America including Alaska and regions of Canada.Human cases of pulmonary dirofilariais have also been reported from Japan, Southern and Eastern Europe, Australia, South America, Japan, Korea, other Southeast Asian countries, and the Middle East. Recent case reports indicate a similar spread to more temperate climates as has been seen in the US. Dogs/canids remain the most important reservoir host but other mammals can serve as competent hosts.

CLINICAL MANIFESTATIONS

In humans, like in animals, the third stage infective larvae, enter subcutaneous tissues. In human tissues, however, appropriate migratory cues are lacking. Case reports describe dirofilaria isolated from numerous sites including skin, orbit, oral cavity, scrotum, musculature, and peritoneal cavity (including ovaries) (8). If the worm enters the venous circulation it may embolize to the pulmonary arteries resulting in infarction and formation of a granulomatous pulmonary nodule. Such nodules have been well described in the literature (4,13,17) and present a diagnostic dilemma, the primary differential being a neoplastic process. Serologic studies have also implicated Dirofilaria as the cause of eosinophilic meningitis (6,14), arthritis (10) and childhood asthma (5).

LABORATORY DIAGNOSIS

Identifying the worm in biopsy or autopsy specimens confirms the diagnosis. Peripheral blood and, in cases of pulmonary dirofilariasis, sputum eosinophilia are common but not diagnostic. Serologic and molecular tests are available and may be important for species identification, especially since most extracted worms have undergone significant degradation by the time of surgery. Any such tests, however, are only used for epidemiological or biological studies and not for the diagnosis of individual cases. D. immitis microfilaria cannot be isolated from human peripheral blood (1).

PATHOGENESIS

Worms isolated from human lung tissue appear to die prior to reaching sexual maturity (3). Pathology observed in dirofilarial infections (e.g. subcutaneous, pulmonary nodules) is generally believed to be due to the host immune response to dying worms and its contents, which may include Wolbachia proteins which are present within Dirofilaria in a symbiotic/mutualistic relationship.

SUSCEPTIBILITY IN VITRO AND IN VIVO

D. immitisis of considerable veterinary importance - causing potentially lethal infections in canines. Effective prophylactic treatment for dogs, however, has been achieved with diethylcarbamazine citrate. Cidal agents are also available for adult worms (thiacetarsamide) and microfilaria (dithiazanine iodide) (12). Ivermectin/pyrantel has also proven very successful in therapeutic trials in dogs (15). In one trial in dogs ivermectin was superior to milbemycin oxime (11). Moxidectin, a newer milbemycin, which, like ivermectin, is a macrocyclic lactone that has exquisite activity in experimental and natural animal infections. Recently, breakthrough infections caused by avermectin and milbemycin resistant dirofiilaria have been documented in dogs treated with prophylactic heartworm medications (2). This would not be expected to affect treatment of human dirofilariasis, which is primarily surgical, but, if confirmed, it may lead to an increase of subclinical infection in reservoir hosts with increased odds of transmission to humans.

ANTIPARASITIC THERAPY

General

To date, following surgical removal of the various lesions caused by adult worms, no specific antifilarial chemotherapy is indicated for human dirofilarial infections (3). Most patients are treated symptomatically with anti-inflammatory agents including steroids and no role for antiparasitic agents has been identified in controlled trials. While the worm has usually died long before extraction, some authors still advocate adding oral treatment with diethylcarbamazine (DEC) (2 mg per kg t.i.d.) over a period of 4 weeks, in some cases even preceded by oral ivermectin (150 mg per kg) to curative surgery (9).

Alternative Therapy

Various filarial parasites including D. immitisare colonized with intracellular symbiotic bacteria (Wolbachia), which may be important in the biology of their filarial hosts (7). There has been recent interest whether treatment with anti-bacterial medications active against Wolbachia could affect survival of filaria. This approach, however, requires more data before it can become recommended therapy.

ADJUNCTIVE THERAPY

Surgical resection is curative and therefore considered the treatment of choice in patients with symptomatic granulomatous disease. Patients with dirofilaria-associated eosinophilic meningitis, arthritis, or childhood asthma may benefit from anti-inflammatory agents including steroids.

ENDPOINTS FOR MONITORING THERAPY

Surgical removal of the parasite is curative. No additional monitoring is recommended.

VACCINES

Experimental canine vaccines are being evaluated but are neither commercially available nor intended for human use (18).

PREVENTION

The current emphasis on heartworm prevention reflects the dependable protection provided by the intermittent administration of macrolide endectocides to domestic dogs. Consistent routine treatment of dogs in endemic areas with commercially available heartworm tablets has the potential to greatly reduce the risk of human infection, however, recent reports of increased resistance and breakthrough infections may threaten the viability of this approach (2). Mosquito repellents offer an additional theoretical benefit.

CONTROVERSIES

Dirofilariasis may cause significant morbidity in humans. Disease, however, is usually driven by the human immune response and not by the parasite itself. Anti-inflammatory agents and surgery should therefore be considered the mainstay of therapy. Some experts still recommend a course of antifilarial therapy before surgery (9). In the authors' opinion antifilarial therapy should be reserved for patients with recent infection suspected of having multiple or live worms.

References

1. Asimacopoulos PJ, Katras A, Christie B. Pulmonary dirofilariasis. The largest single-hospital experience. Chest 1992;102: 851-855.[PubMed]

2. Bourguinat C, Lee AC, Lizundia R, Blagburn BL, Liotta JL, Kraus MS, Keller K, Epe C, Letourneau L, Kleinman CL, Paterson T, Gomez EC, Montoya-Alonso JA, Smith H, Bhan A, Peregrine AS, Carmichael J, Drake J, Schenker R, Kaminsky R, Bowman DD, Geary TG, Prichard RK. Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance. Vet Parasitol 2015:210:167-78.[PubMed]

3. Chitkara RK, Sarinas PSA. Dirofilaria, Visceral Larva Migrans, And Tropical Pulmonary Eosinophilia. Sem Respir Infect 1997;12:138-148. [PubMed]

4. Cifferri F. Human pulmonary dirofilariasis in the United States: A critical review. Am J Trop Med Hygiene 1981;31:302-308. [PubMed]

5.Desowitz RS, Rudoy R, Barnwell JW. Antibodies to canine helminth parasites in asthmatic and nonasthmatic children. Int Arch Allergy Appl Immunol. 1981;65:361-366.[PubMed]

6. Dobson C, Welch JS. Dirofilariasis as a cause of eosinophilic meningitis in man diagnosed by immunofluorescence and arthus hypersensitivity. Trans R Soc Trop Med Hygiene 1974;68:223-228.[PubMed]

7.Genchi C, Sacchi L, Bandi C, Venco L. Preliminary results on the effect of tetracycline on the embryogenesis and symbiotic bacteria (Wolbachia) of Dirofilaria immitis. An update and discussion. Parassitologia 1998;40:247-249.[PubMed]

8.Gutierrez Y, Catellier MJ, Wicker DL, Catallaer M. Extrapulmonary Dirofilaria immitis-like infections in the Western Hemisphere. Am J Surg Pathol. 1996;20:299-305.[PubMed]

9.Jelinek T, Schulte-Hillen J, Loscher T. Human dirofilariasis. Int J Dermatol 1996;35:872-875.[PubMed]

10.Langer HE, Bialek R, Mielke H, Klose J. Human dirofilariasis with reactive arthritis--case report and review of the literature. Klin Wochenschr. 1987;65:746-751.[PubMed]

11.McCall JW, McTier TL, Ryan WG, Gross SJ, Soll MD. Evaluation of ivermectin and milbemycin oxime efficacy against Dirofilaria immitisinfections of three and four months' duration in dogs. Am J Vet Res 1996;57:1189-92.[PubMed]

12. Merrill JR, Otis J, Logan WD Jr, Davis MB. The dog heartworm ( Dirofilaria immitis) in man. An epidemic pending or in progress? JAMA. 1980;243:1066-1068.[PubMed]

13. Nicholson CP, Allen MS, Trastek VF, Tazelaar HD, Pairolero PC. Dirofilaria immitis: a rare, increasing cause of pulmonary nodules. Mayo Clin Proc. 1992;67:646-50.[PubMed]

14. Poppert S, Hodapp M, Krueger A, Hegasy G, Niesen WD, Kern WV, Tannich E. Dirofilaria repens infection and concomitant meningoencephalitis. Emerg Infect Dis 2009;15:1844-6.[PubMed]

15. Pollono F, Pollmeier M, Rossi L. The prevention of Dirofilariarepens infection with ivermectin/pyrantel chewables. Parasitologia 1999;40:457-9.[PubMed]

16. Schmidt GD, Roberts LS. Foundations of Parasitology. St. Louis, Times Mirror/Mosby College Publishing 1989. [PubMed]

17.Shah MK. Human pulmonary dirofilariasis: review of the literature. South Med J 1999;92:276-279.[PubMed]

18.Yoshida M, Nakagaki K, Nogami S, Harasawa R, Maeda R, Katae H, Hayashi Y. Immunologic protection against canine heartworm infection. J Vet Med Sci. 1997;59:1115-21.[PubMed]