Human dirofilariasis Review HUMAN DIROFILARIASIS Th. Kern, G. Ginter, P. Zenahlik and S. Schuller-Petrovic ABSTRACT Human infections with zoonotic filariae are frequently observed throughout the world. Filarial worms of the genus dirofilaria are well known nematodes of carnivorous mammals and can be found in Asia and Africa as well as in the United States and in Europe. Human dirofilariasis is an infection caused by filarial nematodes of the genus dirofilaria . Man is only occasionally .infected. The parasite's life cycle involves uptake of microfilariae from the peripheral blood circulation of infected dogs or cats by mosquitos (Anopheles, Culex, Aedes). Dirofilariasis is transmitted by haematophagous arthropods to man, in whom the nematodes usually die before reaching sexual maturity. Identification of dirofilariae from tissue sections is difficult, but knowledge of the parasite's geographic distribution and patients trave! history may be helpful. KEY WORDS filarial infection, dirofilariasis-parasitology, Dirofilaria repens, subcutaneous nodules Human dirofilariasis is an infection caused by filarial nematodes of the genus dirofilaria usually transmitted by mosquitoes from carnivorous mammals to humans. There are two different forms of clinical manifestation. Man is occasionally infected, the disease manifest itself either as subcutaneous nodules or as pulmonary coin lesions (15,11). Pulmonary dirofilariasis is usually caused by Diro- filaria immitis ( dog heartworm), a common parasite of carnivorous mammals (cats, dogs, foxes and wolves). It is distributed throughtout almost ali trapica! and subtropical countries. The adult male worm measures 120-250 mm, the female worm 220-310 mm in length, both are 1 mm in diameter. Microfilariae acta dermatovenerologica A .P.A. Vol 7, 98, No 3-4 ( first stage larvae) measure 220 - 330 µ,m by 5-6 µ,m. In humans, parasites normally die at the inoculation site in the subcutaneous tissue before reaching sexual maturity, resulting in a granulomatous reaction. In a few cases they reach the right heart ventricle where they die and get passively transported to the lung. The embolization of pulmonary arteries leads to subpleural pulmonary infarction with a granulomatous reaction (11,14,16). Infected persons are asympto- matic in about 50%. In some cases patients show cinical symptoms such as cough and chest pain. Furthermore symptoms as hemoptysis, malaise, myalgia, chills and sometimes fever may be found (1,14). Pulmonary dirofilariasis is often discovered incidentally 179 Human dirofilariasis Figure l. Cross section of Dirofilaria repens swrounded by an inflammatory infiltrate, showing a multilayered cuticle, a well developed musculature and interna! organs. on routine chest radiography. Diagnosis is sometimes difficult since radiological findings only consist of single pulmonaiy nodules and may resemble pulmonary neoplasms (benign, carcinoma, metastasis ), tuberculosis, fungal infections and hamartoma. In many cases only surgical exploration with excisional Jung biopsy leads to the correct diagnosis (1,14). The second manifestation of human dirofilariasis is subcutaneous dirofilariasis, caused by Dirofilaria repens and Dirofilaria tenuis. Dirofilaria tenuis is known as a parasite of the raccoon (procyon lotor). Dirofilaria repens whose principal reservoirs are cats and dogs ( canis familiaris, felis domestica) measures 13 cm in length by 0.5 mm in diameter. It is distributed throughtout Europe, Africa, and Asia. In Europe the parasite is found especially in the mediterranean countries (10,15) (Table 2). Human infections with Dirofilaria repens have been reported from ltaly (7,13), Greece, Spain and other medite- Table l. Dijferential diagnosis of subcutaneus nodules. rranean countries. Clinical symptoms comprise migratoiy erythematous swellings, subcutaneous nodules due to granulomatous reaction in the subcutaneous tissue (9) and pruritus caused by migration of the worm through subcutaneous tissue. Subcutaneous nodules may appear anywhere on the body and have been found on the head, neck, arms, legs, trunk, scrotum, and penis. Even conjunctival and orbita! infections have been described (2,6,11). Identification from histological sections is sometimes difficult but the location of the nodule in the subcutaneous tissue, the diameter of the worm in section, the presence of a multilayered cuticle with fine longitudinal ridges on the external layer and laterni cords, a well developed musculature and the typical arrangement of interna! organs may lead to the correct diagnosis. Figure l. Differential diagnosis comprises inflammatoiy dise- ases, granulomatous diseases, as well as benign and malignant tumors. Also infections with other nematodes must be considered (Dracunculus medinensis, Wuche- reria bancrofti, Loa loa, Onchocerca volvulus, Brugia malayi, Mansonella). (Table 1). There are about 30 species of dirofilarial worms whic:h parasitises various mammals (Table 2). The vector of dirofilariae are mosquitos ( arthropods) of the genera Culex, Aedes and Anopheles. Lice, flies and ticks are possibly also vectors. LIFE CYCLE During their development dirofilarial worms undergo four molts before they reach sexual maturity and become adult worms. Their larval stages are called first, second, third and fourth stage larvae (Tab.3). First stage larvae are called microfilariae. They are released from female worms and are deposited in DIFFERENTlAL DIAGNOSIS OF SUBCUTANEUS NODULES inflammatoiy diseases granulomatous diseases tumors lymphadenopathy nematode infections 180 pyoderma ( abscess, carbuncle) sarcoidosis, granuloma anulare lipama, fibrolipoma, neurofibroma cutaneous metastasis, lymphoma leukemia, metastasis, lymphadenoma Dracunculus medinensis, Wuchereria bancrofti, Loa loa, Onchocerca volvulus, Brugia malayi, Mansonella acta dermatovenerologica A.P.A. Vol 7, 98, No 3-4 Human dirofilariasis Table 2. Geographical distribution of the most important dirofilarial worms. D. immitis (dog, cat, fox, worldwide bear) D. repens (dog, cat, fox) Europe, Africa, Asia D. tenuis (raccoon) North America D. ursi (bear) North America, Japan, Russia D. striata (wild felines) North and South America the peripheral blood stream. There they can be found for severa! months. Microfilariae pass to the intermediate host by ingestion while the insect feeds (blood meal). In the intermediate host, which are mosquitos (arthropods) of the genera Culex, Aedes and Anopheles, larvae molt two times to reach the infective stage. When the mosquito partakes of another blood meal, 3rd stage larvae gain entrance to the definitive host (usually cats and dogs) where they undergo two more molts to reach sexual maturity and become young adults (8,15). Sometimes they are transmitted by chance to humans. Since man is a "deacl end host" and provides an unsuitable environment, dirofilarial worms are not able to undergo their full stages of development and usually die before reaching sexual maturity. The tirne between infection and detection of the Table 3. Life cycle of dirofilarial worms. Host cats and dogs Intermediate host haematophagous arthropods: Culex, Aedes, Anopheles Host cats dogs Man dead end host 1 st stage larva = Microfilariae 2 nd stage larva 3 rd stage larva 4th stage la1va mature worm acta de1matovenerologica A.P.A. Vol 7, 98, No 3-4 nodule depends on the species maturation tirne (11). In case of pulmonary dirofilariasis, adult worms appear in the host's heart particularly in the right ventricle and pulmonary arteries after about 8 to 9 months. The development of Dirofila,ia repens in primates to adolescent or mature stages takes from about 6 months to a few years (4,11). There are some reports where gravid worms have been described. Ali those patients had a defective immunologic system in common. To our knowledge, microfilariaemia has been found only once in a patient with systemic lupus erythematosus, who had taken high doses of cortisone (3,4,11,12). A phenomenon which can be found in the host's peripheral blood stream is the so-called microfilarial periodicity. It means a certain degree of periodicity where a maximum number of microfilariae can be found in the peripheral blood. It enhances the chances of the microfilariae for ingestion by the insect vector. Microfilarial periodicity seems to clepend on physiological changes due to the 24 hour rhythm of the host such as: body temperature, oxygen pressure, carbon dioxid tension or body acidity (8). TREATMENT Surgical removal in many cases is diagnosis and treatment at the same tirne. Additional treatment with diethylcarbamazine in a dose of 3 x 2mg/kg daily over 4 weeks starting with 50 mg/day may be applied. Contraindications are epilepsy ancl renal insufficiency. adult worm microfilaria in blood stream removed from blood stream by arthropods 2 molts achieving infective stage introduced through skin 2 molts maturing to adult worm 181 Human dirofilariasis CONCLUSIONS Human dirofilariasis may be acquired in most mediterranean countries. Migratory skin nodules or singular pulmonary nodules may be the only signs of a possible infection with dirofilarial worms. Identification of dirofilarial worms from tissue sections is difficult; knowledge of the parasite's geographic distribution and the patient's trave! history may be helpful. Growing tourism to foreign countries may lead to an increasing number of dirofilarial infections in regions where the disease is not autochthonous. REFERENCES l. Awe RJ, Jenkins DE, MacLean RA, Dickerson MS. Human Dirofilaria immitis infection - Texas. Morbidity and Mortality Weekly Report, 1974; Nov 2: 378-9. 2. Bardach H, Heimbucher J, Raff M Subkutane Dirofilaria (Nochtiella) repens-Jnfektion beim Menschen - Erste Fallbeschreibung in 6sterreich und Ubersicht der Literatur. Wiener klinische Wochenschrift. 1981; 93(4): 123-Z 3. Beaver PC, Orihel ThC, Leonard G. Pulmonary Dirofilariasis: Restudy of worms reported gravid. Am J Trop med Hyg. 1990; 43(2): 167-9. 4. Bergner T, Loscher T, Barutzki D, Przybilla B. Subkutane Dirofilariasis: Infektion mit Dirofilaria repens Hautarzt. 1990; 41: 265-9. 5. Blackbum CRB, Ma MH Skin reactions of natives in the westem highlands of New Guinea to an antigen prepared from Dirofilaria immitis. Trop geogr Med. 1971; 23: 272-Z 6. Blodi FC, Saparoff GR. Ein Dirofilariagranulom des Lides und der Augenhohle. Klin Mbl Augenheilk. 1977; 171: 222-4. Z Cameri de 1, Sacchi S, Pazzaglia A. Subcutaneous Dirofilariasis in man-Not so rare. Transactions of the Royal Soc Trop Med Hyg. 1973; 67: 887-8. 8. Cheng TC. General Parasitology, New York/London: Academic Press, Jnc. 1973; 668-75. 9. Fini M, Perrone A, Vagliani G, Andreini C, Salvi G, Misuriello G, di Silverio A. Un caso di dirofilariasi umana (D. repens) del funicolo spermatico. Minerva Ural Nefrol.1992; 44(2): 129-31. 1 O. Frank W Parasitologie. Stuttgart: Verlag E Ulmer. 1976; 287-94 and 356-8. 11. MacDougall LT, Magoon CC, Fritsche TR. Dirofilaria repens manifesting as a breast nadute. Am J Clin Pathol 1992; 97: 625-30. 12. Pacheco G, Schofield jr H Dirofilaria tenuis containing microfilariae in man. Am J Trop Med Hyg. 1968; 17:180-2. 13. Pampiglione S, Canestri-Trotti G, DeSantolo GP, Fabbri F, Garavelli PL, Mastinu A, Rivasi F, Schmid C. Dirofilariasi sottocutanea umana: 8 nuovi casi in Italia Settentrionale. Pathologica. 1994; 86(4): 396-400. 14. Ro JY, Tsakalakis PJ, White VA, Luna MA, Chang-Tung EG, Green L, Cribbett L, Ayala AG. Pulmonary Dirofilariasis: The great imitator of primary ar metastatic lung tumor. Human Pathology. 1989; 20: 69-76. 15. Stemberger H Wurmerkrankungen des Menschen. 1st ed, Wien: Facultas-Universitatsverlag. 1986; 59-60. 16. Tomieporth N, Brandis A, Vogel B, Disko R. Autochthone pulmonale Dirofilariose in Europa. Dtsch Med Wschr. 1990; 115: 15-9. AUTHORS' ADDRESSES 182 Thomas Kern, MD, Department of Dermatology, Auenbruggerplatz 8, University of Graz, A-8036 Graz, Austria Gabriele Ginter, MD, professor of dermatology, same address Sanja Schuller Petrovič, MD, professor of dermatology, same address acta dermatovenerologica A.P.A. Vol 7, 98, No 3-4