DISEASES OF THE ORAL CAVITY CAUSED BY PROTOZOA - Capítulo do livro: Oral Diseases. Textbook and Atlas. Lotti, TM, Parish LC & Rogers III RS (eds.) Berlin: Springer-Verlag;1999:122-125

Marcia Ramos-e-Silva, MD, PhD

Associate Professor of Dermatology - Oral Dermatology Clinic Supervisor, HUCFF-UFRJ, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Protozoa are unicellular organisms that range in size from submicroscopic to macroscopic. They are the simplest organisms of the animal kingdom; most are free living, but some have parasitic existence. Diseases caused by protozoa rarely produce oral lesions, except for the muco-cutaneous form of leishmaniasis found in South and Central America, discussed in the chapter 'Oral lesions of Tropical Diseases'.

There are only very few case reports in the medical literature of amebiasis, American trypanosomiasis, toxoplasmosis and trichomoniasis producing oral or perioral lesions.

AMEBIASIS

DEFINITION: Amebiasis is an intestinal parasitic disease that may sometimes affect the skin, specially perianal and genital areas. Oral manifestations, although possible, are extremely rare.

ETIOLOGY: This disease is caused by a very common and worldwide intestinal unicellular parasite, Entamoeba histolytica, the only human pathogenic species of this genus. The invasive form found in the tissues is a 20 to 40mm elongated cell, with pseudopods on its surface.

Another species, Entamoeba gingivalis, morphologically very similar to E. histolytica, is often found in the mouth where it lives as a commensal. This species shows great proliferation when associated to inflammatory processes caused by other microorganisms.

PATHOGENESIS: In humans there are two pathogenically important distinct life cycle phases of Entamoeba histolytica: the trophozoite and the cyst. The trophozoite or invasive form produces the disease, penetrates the tissues, and sometimes blood vessels, and can be found inside the wall of the colon, specially sigmoid and rectum. The cyst or infectious form is released with human feces to the outside where it can survive for several days, and is able to contaminate water, food and fomites. Intestinal amebiasis, usually manifested as diarrhea or dysentery, is produced by the ingestion of these cysts, that turn into trophozoites in the ileum, being able to penetrate again the intestinal wall. Cutaneous and mucosal amebiasis may be provoked by direct inoculation from intestinal amebiasis, by continuity from amebic hepatic abscess, after infested colon or liver surgeries, hematogenic or lymphatic spread, and oral-anal or genito-anal contact. Poor hygiene, promiscuity, poverty and immunosuppression facilitate the disease, mainly in tropical areas.

ORAL MANIFESTATIONS: Entamoeba gingivalis oral infection may be suspected in the presence of generalized dental mobility, specially in young patients, enlarged tongue, fetid halitosis, vivid red color, frequent hemorrhages and pruritus of gingiva, with no other causes. Cutaneous, genital, perianal or very rarely oral lesions provoked by Entamoeba histolytica although extremely uncommon when present are characterized by a single or few very painful inespecific serpiginous and destructive ulcers.

ASSOCIATED FINDINGS: Oral manifestations of Entamoeba histolytica infection may only be present in the advanced chronic form which shows manifestations in various organs. Skin and mucosal lesions are almost always associated to intestinal amebiasis manifested by dysentery. There may be constitutional symptoms ranging from mild, as loss of appetite, fever, leukocytosis and dehydration, to severe, as massive intestinal hemorrhage, bowel perforation and peritonitis. The most common extraintestinal manifestation is the hepatic abscess.

MICROSCOPIC FINDINGS: In tissues the trophozoites, with a basophilic and elongated cytoplasm, single eccentric nucleus and central spherical cariosome, are very difficult to be observed. In cutaneous and mucosal lesions they are more easily seen in biopsies of the borders rather than the center of the ulcer.

DIAGNOSIS: Entamoeba gingivalis may be recovered from dental plaques. The motile Entamoeba histolytica trophozoites may be found on lesion scrapings and the cysts on feces parasitologic examination. Other useful tests are hemagglutination, complement fixation, ELISA, immunoperoxidase, and specially indirect immunofluorescence.

DIFFERENTIAL DIAGNOSIS: All diseases that cause periodontal disease or large oral ulcerations, specially when accompanied by pain, such as herpes simplex, donovanosis, tuberculosis, and squamous cell carcinoma, have to be included in the differential diagnosis. The main differentiation is histopathologic by the occurrence of trophozoites.

TREATMENT: Complete cure can be rapidly achieved in 7 to 20 days with metronidazole, 20 to 40mg/kg/day, divided in three daily doses, for up to 8 days. Tinidazole, in a single daily dosage, 2g for adults and 50 to 60mg/kg for children, for 3 to 5 days, also shows good and fast results. Intravenous or intramuscular dehydroemetine hydrochloride, the drug of choice in the past, is cardiotoxic. Di-iodohydroxyquinoline, paromomycin and diloxanide furoate can also be used. Severe dysentery associated to mucosal or cutaneous involvement requires support measures.

BIBLIOGRAPHY
1. Arenas R. Dermatologia. Atlas, diagnóstico y tratamiento. 2ed. Mexico:McGraw-Hill Interamericana 1996:375-6.
2. Bryceson ADM & Hay RJ. Parasitic worms and protozoa. In: Champion RH, Burton JL, Ebling FJG. eds. Rook, Wilkinson, Ebling Textbook of Dermatology. 5ed. London:Blackwell Scientific, 1992:1217-64.
3. Dorland's Illustrated Medical Dictionary. 28ed. Philadelphia:Saunders 1994:1373.
4. Farah FS, Klaus SN, Frankenburg S, Klion AD, Nutman TB. Protozoan and helminth infection. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg JM, Austen KF. Dermatology in General Medicine. 4ed. New York:McGraw-Hill, 1993:2769-87.
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12. Richman TB, Kerdel FA. Amebiasis and trypanosomiasis. Dermatol Clin 1989;7(2):301-11.
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14. Schaller KF. ed. Color Atlas of Tropical Dermatology and Venereology. Berlin:Springer-Verlag, 1994:103-14.

Figure 1: Inoculation lesion on the eyelid - Romaña's sign (Courtesy of João Dias & Luís Rey, Brazil)
Figure 2: Trypanosoma cruzi in blood (Courtesy of Luís Rey, Brazil)
Figure 3: Reduviid bug (Courtesy of Luís Rey, Brazil)

AMERICAN TRYPANOSOMIASIS / CHAGAS' DISEASE

DEFINITION: Trypanosomiasis is a tropical and mainly rural parasitic disease of blood and various organs. There are two different entities: the African, caused by trypanosomes of the T. brucei group (T. gambiense and T. rhodesiense), transmitted by tsetse flies, also called sleeping sickness, and the American, known as Chagas' disease. Inoculation lesions on the lips can sometimes be observed in American trypanosomiasis.

ETIOLOGY: Chagas' disease is produced by a hemoflagellated protozoan, Trypanosoma cruzi (Chagas, 1909), affecting humans and various domestic or wild mammals that act as reservoirs. It is transmitted by bloodsucking invertebrates of the order Hemiptera, genera Triatoma, Panstrongylus and Rhodnius, called reduviid, assassin or kissing bugs and 'barbeiro' in Brazil. Transfusional and congenital infection are also possible, although very rare.

PATHOGENESIS: Trypanosoma cruzi goes through various stages in its life cycle. The trypomastigota or flagellated form is observed in the blood of the definitive vertebrate host, and amastigota in cells of various tissues. Other phases are only seen in the vector. The insect bites the definitive host, and deposits infected stools on the skin or mucosa. Transmission occurs through the bite wound itself, small skin cuts and abrasions or even through intact eye or lip mucosa.

ORAL MANIFESTATIONS: Mouth lesions are mainly seen on the lips and are similar to the skin chagoma. They are characterized by an erythematous nodule, swelling or ulcer at the site of inoculation which, in general, heals spontaneously in about three weeks.

ASSOCIATED FINDINGS: Inoculation occurs during the night, when the insect is active and needs to feed. Lesions appear on uncovered areas, usually the face. Romaña's sign, an unilateral eyelid edema associated to dacryoadenitis (inflammation of the lacrimal gland), occurs in 80% of the cases, five to 10 days after transmission, and is the most characteristic skin lesion. The acute phase, more prevalent in children, progresses with high fever, headache, morbilliform rash, regional lymphadenopathy, hepatosplenomegaly and acute meningoencephalitis; death occurs frequently in this phase. The subacute form produces mild fever, malaise, and generalized lymphadenopathy. Cardiac (chagasic miocarditis) and gastrointestinal (megaesophagus and megacolon) manifestations occur in the chronic phase.

MICROSCOPIC FINDINGS: In blood smears, the trypomastigota form is a spindle shaped elongated and mobile protozoan, with an undulating membrane and an anterior flagelllum, measuring 15 to 20mm long. The form seen in the tissues, amastigota, measures 1.5 to 4.0mm in diameter. It is an ovoid and immobile obligatory intracellular parasite, found in groups specially inside muscle fibers.

DIAGNOSIS: During the acute phase, direct examination of Giemsa stained blood smears, imprints of skin or lymphnode biopsy can easily show the parasite. They can also be demonstrated by blood culture in NNN media, or animal inoculation.
Xenodiagnosis of Brumpt is also helpful. For this an uninfected reduviid bug is allowed to bite and feed on the forearm of the suspect patient; 30 to 60 days later the insect's feces are examined, searching for the infective form.
During the chronic phase, the Machado-Guerreiro complement fixation test using antigens of cultured T. cruzi is most useful. ELISA, hemagglutination, indirect immunofluorescence and PCR can also diagnose the disease.

DIFFERENTIAL DIAGNOSIS: Mucosal inoculation lesion has to be distinguished from other diseases that produce nodules, swellings and ulceration, such as pyoderma, leishmaniasis, myiasis, angioedema, and specially primary syphilis chancre which also heals spontaneously.

TREATMENT: At present oral trypanocidal medications such as benzonidazole, 5 to 7mg/kg divided in two daily doses for 30 to 60 days, and nifurtimox 6 to 10mg/kg, divided in three daily doses for 60 to 120 days, are the most effective, although both may cause serious side effects. Besides medication, improvement of rural housing conditions and control of vector proliferation are extremely important in this disease.

BIBLIOGRAPHY
1. Alyssa Kim Y, Schwartz R. The United States of America. In: Parish LC, Millikan LE. Global Dermatology - Diagnosis and management according to geography, climate, and culture. New York:Springer-Verlag. 1994:45-50.
2. Caumes E, Danis M. Trypanosomiases. In: Piérard GE, Caumes E, Franchimont C, Arrese Estrada JA. Dermatologie Tropicale. Brussels:Éditions de l'Université de Bruxelles, 1993:335-40.
3. Farah FS, Klaus SN, Frankenburg S, Klion AD, Nutman TB. Protozoan and helminth infection. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg JM, Austen KF. Dermatology in General Medicine. 4ed. New York:McGraw-Hill, 1993:2769-87.
4. Kerdel-Vegas F. American trypanosomiasis. In: Champion RH, Burton JL, Ebling FJG. eds. Rook, Wilkinson, Ebling Textbook of Dermatology. 5ed. London:Blackwell Scientific, 1992:1250-1.
5. Nicodemo EL, Nicodemo AC, Amato Neto V, Sampaio S. American trypanosomiasis (Chagas' disease). In: Canizares O, Harman R. Clinical Tropical Dermatology. 2ed. Boston:Blackwell Scientific, 1992:286-92.
6. Piette E. Revue générale des parasitoses d'intérêt maxillo-facial. Acta Stomatol Belg 1989;86(3):175-210.
7. Rey L. Parasitologia. Parasitos e doenças parasitárias do homem nas Américas e na África. 2ed. Rio de Janeiro:Guanabara Koogan, 1991:128-69.
8. Richman TB, Kerdel FA. Amebiasis and trypanosomiasis. Dermatol Clin 1989;7(2):301-11.
9. Schaller KF. ed. Color Atlas of Tropical Dermatology and Venereology. Berlin:Springer-Verlag, 1994:103-14.

TOXOPLASMOSIS

DEFINITION: Toxoplasmosis is an acute or chronic, widespread and incidental disease of large mammals and humans. It is caused by a tiny sporozoon whose definitive hosts are cats.

ETIOLOGY: The obligate intracellular protozoan Toxoplasma gondii is transmitted by feces of the infected cat (definitive host) and is virtually capable of infecting all tissues except red blood cells.

PATHOGENESIS: Toxoplasma gondii is transmitted to humans in the form of oocysts present in the infected cat's feces, through contaminated soil, direct exposure to infected feces, tissue cysts in raw infected meat (specially pork), or tachyzoites (proliferating forms) in blood. The parasite invades the reticulo-endotelial system and the endothelium of blood vessels, causing a necrotic granuloma.

ORAL MANIFESTATIONS: Cervical lymphadenopathy is the most common form of acquired toxoplasmosis, although other forms of oral and perioral manifestations are seldom seen. Tongue, larynx or pharynx myositis as well as parotid swelling may occur in the acquired form; enamel hypoplasia can be observed in congenital infection.

ASSOCIATED FINDINGS: Most human infections are asymptomatic. When symptoms occur they range from a mild self-limited disease, clinically resembling mononucleosis, to a fulminating disseminated condition that may cause extensive damage to the brain, eyes, skeletal and cardiac muscles, liver, and lungs, specially in AIDS patients. Severe manifestations, causing intrauterine death, serious fetal damage, deafness or blindness, can be seen in transplacental infection. Chorioretinitis may be associated with all forms, but is usually a late sequel of congenital toxoplasmosis.

MICROSCOPIC FINDINGS: Histopathology is not diagnostic, but an enlarged lymphnode biopsy showing follicular hyperplasia, the characteristic 'immature sinus histiocytosis' and scattered foci of light pink histiocytes, very evident in a dense infiltrate of lymphocytes, with a lymphoma aspect, are highly suggestive of the disease.

DIAGNOSIS: Confirmation can be achieved by demonstration of Toxoplasma gondii in lymphnode, or any other infected organ or fluid. Serology by means of Sabin-Feldman dye test, hemagglutination, complement fixation, indirect immunofluorescence, or ELISA are very useful. Specific IgM positivity indicates active disease.

DIFFERENTIAL DIAGNOSIS: Cervical lymphadenopathy of toxoplasmosis has to be distinguished clinically and histologically from other causes of lymphnode enlargement specially lymphomas such as Hodgkin's disease.

TREATMENT: The available drugs for toxoplasmosis are pyrimethamine, 25mg/day, and sulphonamides, 2 to 4g/day. They act synergistically and are usually associated. Although very effective this association has serious side effects, such as impairment of folic acid metabolism, that contraindicates its use in immunologically competent and asymptomatic patients.

BIBLIOGRAPHY
1. Appel BN, Mendelow H, Pasqual HN. Acquired toxoplasma lymphadenitis. Oral Surg Oral Med Oral Pathol 1979;47(6):529-32.
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6. Scully C, Flint SR, Porter SR. Oral diseases. 2ed. Singapore:Martin Dunitz, 1996:99.

TRICHOMONIASIS / TRICHOMONOSIS

DEFINITION: Trichomoniasis is a parasitic disease caused by flagellated protozoa of the genus Trichomonas, found mainly in the intestinal and genitourinary tracts of various invertebrates and vertebrates.

ETIOLOGY: Three species of Trichomonas may affect humans: T. vaginalis, a genitourinary parasite, T. hominis, of the intestinal tract, and T. buccalis or tenax, in general, a commensal of the mouth.

PATHOGENESIS: In the mouth, T. tenax is most often seen in the tartar formed around teeth, cavities of carious teeth, pockets associated with periodontal disease, and tonsilar crypts. Its presence is correlated to bad oral hygiene.

ORAL MANIFESTATIONS: This parasite has been frequently related to lesions of periodontium, the tissue that surrounds the tooth. Its abnormal proliferation is associated to the development of periodontal pockets, chronic inflammatory reaction, and eventually destruction and loss of teeth in severe cases.

MICROSCOPIC FINDINGS: T. tenax are found in scrapings from periodontal pockets and are characterized by four anterior flagella and an undulating membrane.

TREATMENT: All species of genus Trichomonas can be easily treated by metronidazole, 250mg, bid or tid for 7 to 10 days. Local hygiene improvement and appropriate treatment of periodontitis are more important for oral trichomoniasis than the administration of systemic drugs.

BIBLIOGRAPHY
1. Azulay RD, Azulay DR. Dermatologia. 2ed. Rio de Janeiro:Guanabara Koogan, 1997:232.
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