CASE REPORT

Visceral Larva Migrans Due to Ascaris suum WhichPresented with Eosinophilic Pneumonia and Multiple Intra-hepatic Lesions with Severe Eosinophil Infiltration -Outbreak in a Japanese Area Other than Kyushu- Ayako Sakakibara, Kenji Baba, Sayaka Niwa, Takeo Yagi, Hideo Wakayama, Kazuhito Yoshida, Tadashi Kobayashi, Takio Yokoi*, Kazuo Hara*, Makoto Itoh** and Eisaku Kimura**

Abstract tion. Here, wereport a case of visceral larva migrans due to Ascaris suumconsidered to be the result of the patient's unique A 32-year-old man presented with the chief complaint dietary habits. This is a case ofAscaris suum larval infection of severe cough. Examination of peripheral blood showed occurring in an area other than Kyushu. The importance of a marked increase in eosinophils. Chest CTdemonstrated constant monitoring of the epidemiology of this disease can- multiple ground glass opacities in both lungs. Broncho- not be overestimated. alveolar lavage showed abundant eosinophils. Abdominal CTdemonstrated multiple low attenuation areas in the liver. Case Report Liver biopsy with ultrasonography revealed severe eosino- phil infiltrations around the portal veins. Serologically, a A32-year-old manwas admitted to our hospital because of multi-dot enzyme linked immunosorbent assay (DOT- severe non-productive coughthat had been sustained for one ELISA) and ELISA inhibition test using microtiter plates month and had led to serious sleep disorder. He had no rel- were positive for Ascaris suum. Thus, visceral larva migrans evant history or family history. He was born in Aichi prefec- due to Ascaris suumwas diagnosed. Outbreaks of this dis- ture and had no history of residence in the Kyushu area. Fur- ease in Japan have previously been confined to the Kyushu thermore, he had no experience of traveling abroad. Hewas a area. The present case which occurred outside that area, mechanic at a car-service station, and had a lot of pets, includ- illustrates the importance of constant attention to the epi- ing 2 dogs, 2 cats and 10 hamsters. He always ate vegetables demiology of this disease. cultivated at home using organic fertilizer. Furthermore, he often (Internal Medicine 41: 574-579, 2002) ate various kinds of raw meat including cattle liver, poultry meat, whale meat, horsemeat and venison. Key words: albendazole, eosinophilia, bronchoalveolar lavage, On admission, hematological examination of peripheral granuloma with eosinophil infiltration, parasite, blood showed a marked increase in eosinophils ( 10,773/|il) and dietary habit a high titer (20,283.5 IU/ml) of total IgE. The IgE antibody for specific allergen (IgE radioallergosorbent test, RAST) was positive for ascaris (class 3) and hamster (class 1) (Table 1). A stool specimen was negative for occult blood or parasite eggs. Introduction Chest X-ray did not reveal any apparent abnormalities, how- ever chest computed tomography (CT) demonstrated focal and In Japan, parasitic infections decreased markedly following faint ground glass opacities in both lungs (Fig. 1). Furthermore, improvements in sanitation. However,they are again drawing abdominal CTshowedmultiple low attenuation areas in the considerable attention, as recently the incidence of parasitic liver (Fig. 2). infection has been on the increase most likely due to increas- Examination with a flexible fiberoptic bronchoscope showed ing overseas travel, diversification of Japanese dietary habits, no endoscopic abnormalities. Bronchoalveolar lavage (BAL) pet boom, as well as the increasing use of fertilizer for cultiva- was performed on the right upper lobe, and cytologic exami- From the Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, *Division of Pathology, Aichi Medical University Hospital and **Department of Parasitology, Aichi Medical University School of Medicine, Nagakute Received for publication October 2, 2001 ; Accepted for publication February 24, 2002 Reprint requests should be addressed to Dr. Kenji Baba, the Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute, Aichi 480-1 195

574 Internal Medicine Vol. 41, No. 7 (July 2002) Visceral Larva Migrans by Ascaris suum nation showed no abnormalities including fungi, acid-fast ba- diagnosed. cilli or other microorganisms. However,abundant eosinophils A parasiticide (albendazole; Eskazole® 200 mg per os three were present in the BALfluid (Table 1). times a day, every other week), was begun, with a plan to con- Liver biopsy was carried out with ultrasonography, and re- tinue treatment for 6 months. The severe cough and low at- vealed severe eosinophil infiltrations especially in the portal tenuation areas in the liver on abdominal CTdisappeared after area (Fig. 3). No microorganisms were found in the biopsy 2 months. The eosinophil count in peripheral blood also de- specimens (Fig. 3). creased. However, the pulmonary infiltrates on chest CT re- These findings raised the possibility of parasite infection mained, and the antibody titer for Ascaris suum was still high. and thus multi-dot enzyme linked immunosorbent assay (DOT- Four monthsafter the start of therapy, mild impairmentof liver ELISA) (1) was performed in order to identify the causative function appeared in the form of elevation of plasma aspartate parasite. The assay was strongly positive for Ascaris suumand aminotransferase (AST)and plasma alanine aminotransferase weakly for Toxocara canis and Strongyloides stercoralis (Fig. (ALT) to double the upper normal limit, and consequently 4). An ELISA inhibition test using microtiter plates (2) was therapy was suspended. One month later, the liver function had also performed and was strongly positive for Ascaris suum. recovered to normal, and the therapy was resumed. At this time, Thus, visceral larva migransdue to Ascaris suuminfection was the eosinophil count in peripheral blood appeared to increase again. By the time the total period of albendazole administra- tion reached 6 months, the pulmonary infiltrates had completely Table 1. Laboratory Data on Admission disappeared, and the eosinophil count in peripheral blood and P eriph eral b loo d : the serum antibody titer for Ascaris suumhad substantially White blood cells 1 8,900/llI decreased. Accordingly, the therapy was stopped (Fig. 5). To stab neutrophils 0 % date, follow-up examination has not revealed deterioration. segmented neutrophils 2 3.C lym p ho cytes 17 .0% Discussion m o no cytes 2. 0% eo sino ph ils 5 7. 0% Humansare not often infected by Ascaris suum, due to the b asoph ils .0% Red blood cells 474x 1 04/ul host specificity of this parasite for the pig (3). However, once a H em o glob in 14.4 g/dl humanis infected, the Ascaris suumlarva migrates amongthe P latelet 29.7xl 04/ul various organs without growth, resulting in the clinical mani- festation knownas visceral larva migrans (VLM)(4-6). Blood chemistry: The clinical manifestation of VLM,which was firstly re- T otal p rotein 8.5 g/dl ported by Beaver in 1952 (7), is characterized by long-stand- A lbu m in 4.4 g/dl ing hypereosinophilia with hepatomegaly and/or pneumonia T otal b iliru b in 0.58 mg/dl (6). There are a wide variety of non-specific symptoms, in- Aspartate aminotransferase (AST) 30 IU// cluding general malaise, cough and liver function disorders (8). Alanine aminotransferase (ALT) 3 7 IU // Ocular lesions have also been reported in some cases (9). De- Lactate dehydrogen ase (LDH) 650 IU// finitive diagnosis for parasitic diseases should be madeon the Alkaline phosphatase (ALP) 314 IU/J detection of worms and/or eggs from patients. However, it is y-G lutam yl transpep tida se (y-G T P ) 18 IU // N a 136 mE q/l extremely difficult in cases of VLM,since nematode larvae are K 4.6 mEq// very tiny and move rapidly. Actually, VLMhad previously been c ¥ 103 mEq // diagnosed only at autopsy. Recently, a method for immunodia- C a 9.1 mg/dl gnosis, i.e., ELISAinhibition test was established. The useful- G lu co se 98 mg/dl ness of this method has already been shown for the differential diagnosis between Paragonimus westermani and P. miyazakii Sero lo g ical test: infections (10). This method has been used for identification T o tal Ig E 20,283.5 IU/ml of causative parasites species. Discrimination of ascarid para- I g E R A ST ham ster; class 1 site with fine specificity has also been possible by the ELISA asc aris; class 3 inhibition test (2). Thus, diagnosis for VLMis practically pos- C-reactive protein 0.28 mg/dl sible by the combinations of symptoms, laboratory data and Cold hemagglutinin x 2 56 the immunodiagnosis (2, ll).

Bronchoalveolar lavage fluid In the present case, the clinical symptomsand signs were T otal c ell cou nt 7 00/u l compatible with those of VLM,and comprised 1) severe cough L ym p ho cytes 3.C with remarkable eosinophilia that had persisted for a long pe- M acrop h age 29 .0% riod, 2) detection of the specific antibody for Ascaris suum by E o sino ph ils 68 .0% DOT-ELISAand microplate ELISA inhibition test, and 3) eo- C D 4 /8 .0 8 sinophilic pneumonia and intra-hepatic multiple granuloma le- sions with marked eosinophil infiltration.

Internal Medicine Vol. 41, No. 7 (July 2002) 575 Sakakibara et al

Figure 1. Chest CT showing multiple focal ground glass opacities (arrows) in both lung fields.

Thetreatment of choice is a course of ivermectin or albenda- mission (18, 19). Ascaris suum is known to cause VLMwith zole (12, 13). Long-term, high-dose administration of albenda- the manifestation of severe eosinophilic pneumoniain cattle zole may be effective on refractory VLM(12). Accordingly, (20). In animal models, chicken livers and lungs were proven we planned to give albendazole (600 mg/day per os every other to be important sources of infection with Ascaris suum(21). week) over 6 months in the present case. It is reported that in In the present case, we first suspected the origin of the As- small mammalsa high percentage of the larvae persist in the caris suuminfection to be the vegetables cultivated at home, infective stage without growth or development, throughout the and consequently examined the soil and fertilizer. However, life span of the host, and that in monkeysthey remain alive no pathogens were detected. On the other hand, the patient also and infective for at least 10 years (14). Although the symp- regularly ate raw cattle liver and raw poultry meat, a habit we toms and clinical signs improved with this therapy, we needed believe to be the most likely cause of the present illness. continuous monitoring to detect early relapse of symptomsand In Japan, several cases ofVLMby Ascaris suum have been signs of VLM.Under the present circumstances, the determi- reported since 1994 (15, 16, 22, 23), all of which involved resi- nation of dosage schedules of this drug was by necessity based dents of the pig raising region in southern Kyushu. Ascaris entirely on experience. However, Ascaris suuminfection can suum infection in Japan was usually thought to be endemic in be life threatening whena large numberof the eggs are in- Kyushu. However, an outbreak of this disease outside Kyushu gested (4), and therefore, experimental clarification of the op- area has recently been reported and is suspected to be due to timal therapy for VLMis of paramount importance. the dietary habit of regular intake of raw meat (24) as well as Albendazole is reported to induce serious functional impair- in the present case. As the cases including the present case ment of the liver withjaundice in 5%of patients (15). Simi- illustrate, the possibility of dietary habit as a cause of this dis- larly, in the present case, slight impairment of liver function ease suggests that Ascaris suuminfection mayoccur through- occurred 4 months after administration of albendazole began out Japan. Distribution of raw meat as merchandise mayalso and transient cessation of this drug was necessary for 1 month serve as warning of distribution of this disease. Further de- until recovery of liver function. Thus, periodic examination of tailed investigation of the epidemiology ofAscaris suumin- liver function during albendazole therapy is essential. cluding routes of transmission may be necessary in this coun- Oneroute of transmission ofAscaris suumis believed to be try. the ingestion of vegetables, cultivated using pig excrement as fertilizer (5, 16, 17). The intake of raw meat infected with As- caris suumhas also been suspected as another route of trans-

576 Internal Medicine Vol. 41, No. 7 (July 2002) Visceral Larva Migrans by Ascaris suum

Figure 2. Abdominal CT showing multiple intra-hepatic low attenuation areas, where the CTnumbers are almost identical to those of muscle tissue.

Acknowledgements: Weare very grateful to Professor Yukifumi Nawa, Department of Parasitology, Miyazaki Medical College, for measurement of serumAscaris titer with the microplate ELISAinhibition test and for advice concerning therapy. Wealso thank Professor Aiji Noda, Division of General Medicine, Department of Internal Medicine, Aichi Medical University and Dr. Hideo Murayama, Division of Gastroenterology, Department of Internal Medi- cine, Aichi Medical University, for their technical support with the liver bi- opsy. References

1) Itoh M, Sato S. Multi-dot enzyme-linked immunosorbent assay for se- rodiagnosis of trematodiasis. Southeast Asian J Trop MedPublic Health 21: 471-474, 1990. 2) Maruyama H, Noda S, Choi W-Y, Ohta N, NawaY. Fine binding speci- ficities to Ascaris suumand Ascaris lumbricoides antigens of the sera Figure 3. Pathology of liver biopsy specimen demonstrates from patients of probable visceral larva migrans due to Ascaris suum. granulomatouslesions with severe eosinophil infiltrations Parasitol Intern 46: 181-188, 1997. around portal vein (arrow). No worm bodies are found (HE 3) Takata I. Experimental infection of man with ascaris of man and the pig. stain, x40). KitasatoArch Exp Med 23: 49-59, 1951. 4) Phills JA, Harrold AJ, Whiteman GV, Perelmutter L. Pulmonary infil- trates, asthma and eosinophilia due to Ascaris suum infestation in man. New Engl J Med 286: 965-970, 1972. 5) Crewe W, Smith DH. Humaninfection with pigAscaris (A. suum). Ann Trop Med Parasitology 65: 85, 1971.

Internal Medicine Vol. 41, No. 7 (July 2002) 577 Sakakibara et al

DOT-ELISA Sheet

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P atient 21 ParagonimusParagonimus miyazakiiwestermanii 3 Fasciola hapatica 7 4 Clonorchis sinensis 65 SchistosomoToxocara cantsjaponicum 7 Ascaris suum 8 Trichinella sp. 9 Strongylus stercoralis 10 Angiostrongylus cantonensisll Gnathostoma doloresi 12 Ancylostoma caninum 13 Anisakis sp. 1415BrugiaDirofilariapahangiimmitis 16 Diphyllobothrium sp. >witHn

Figure 4. Multi-dot enzyme linked immunosorbent assay with the patient's serum shows a positive result for Ascaris suum (arrow). The numberof the cell in the schema corresponds to that of each organism. The serum was also weakly positive for Toxocara canis. The serum was verified to be strongly positive for Ascaris suumby the microplate ELISAinhibition test.

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I y) m u n i m i (A6l0b0e nmdga/zdoal 10,7 73///l A n ti-A sca ri s su u m E o sin o p h ils ( 5 7 - - % ) A n t i b o d y t i t e r O V u i) � ( X 25,600 dilution) (O D ) 1- 1.5

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Figure 5. Clinical course of the patient. Antibody titers to Ascaris suum are the results of the microplate ELISAinhibi- tion test.

578 Internal Medicine Vol. 41, No. 7 (July 2002) Visceral Larva Migrans by Ascaris suum

6) Beaver PC. The nature of visceral larva migrans. J Parasitol 55: 3-12, 16) Matsuyama W, Mizoguchi A, Iwami F, Kawabata M, Osame M. Acase of 1969. pulmonary infiltration with eosinophilia caused by Ascaris suum. J Jpn 7) Beaver PC, Snyder CH, Carrera GM, Dent JH, Lafferty JW. Chronic eo- Respir Soc 36: 208-212, 1998 (in Japanese, Abstract in English). sinophilia due to visceral larva migrans; Report of three cases. Pediatrics 17) MaruyamaH, Noda S, Nawa Y. An outbreak of visceral larva migrans 9: 7-19, 1952. due to Ascaris suum in Kyushu. Clin Parasitol 7: 82-84, 1996 (in Japa- 8) van Kanpen F, Buijs J, Kortbeek LM, Ljungstrom I. Larva migrans syn- nese). drome: toxocara, ascaris, or both? Lancet 340: 550-551, 1992. 1 8) Matsushita R, TaharaY, YamamotoS, et al. Acase of visceral larva migrans 9) Taylor MRH, Keane CT, O'Connor P, Girdwood RWA, Smith H. Clinical (VLM)with multiple intra-hepatic nodular lesions due to Ascaris suum. features ofcovert toxocariasis. Scand J Infect Dis 19: 693-696, 1987. Kanzo 38: 730-734, 1997 (in Japanese). 10) Okamoto M, Miyake Y, Shouji S, et al. A case of severe paragonimiasis 19) Ito K, Sakai K, Okajima T, et al. Three cases of visceral larva migrans miyazakii with lung and skin lesions showing massive egg production in due to ingestion of raw chicken or cow liver. Nippon Naika Gakkai Zasshi sputum and faeces. Jpn J Parasitol 42: 429-433, 1993. 75: 759-766, 1986 (in Japanese). 1 1) Ogilvie BM, de Savigny D. Immune response to nematodes. in: Cohen S. 20) McLennanMW,Humphris RB, Rac R. Ascaris suum pneumonia in cattle. Warren KS, Eds. Immunology of Parasitic Infections, 2nd ed. Blackwell Aust Vet J 50: 266-268, 1974. Scientific Publications, London, 1982: 715-757. 21) Permin A, Henningsen E, Murrell KD, RoepstorffA, Nansen P. Pigs be- 12) Caumes E, Carriere J, Datry A, Gaxotte P, Danis M, Gentilini M. A ran- comeinfected after ingestion of livers and lungs from chickens infected domized trial of ivermectin versus albendazole for the treatment of cuta- with Ascaris of pig origin. Int J Parasitol 30: 867-868, 2000. neous larva migrans. AmJ Trop Med Hyg 49: 641-644, 1993. 22) Maruyama H, Nawa Y, Noda S, Mimori T, Choi W-Y. An outbreak of 13) Bhatia V, Sarin SK. Hepatic visceral larva migrans: evolution of the le- visceral larva migrans due to Ascaris suum in Kyushu Japan. Lancet 347: sion, diagnosis, and role of high-dose albendazole therapy. AmJ Gastroen- 1766-1767, 1996. terol 89: 624-627, 1994. 23) Miki T, Miyazono Y, Tyujo M. CT findings of the hepatic nodular lesions 14) Beaver PC. Zoonoses, with particular reference to parasites of veterinary by infection ofAscaris suum; a case report. Jpn J Clin Radiol 41: 1525- importance, in: Soulsby EJL, Ed. Biology of Parasites, Emphasis on Vet- 1528, 1996. erinary Parasites, Academic Press Inc., New York, 1966: 21 5-227. 24) Hata T, Tateishi H, Tono T, Okamoto S, Okamura J, Monden T. Hepatic 15) El-Mufti M, Kamag A, Ibrahim H, et al. Albendazole therapy of hydatid eosinophilic granulomadue to visceral larva migrans ofAscaris suum-a disease: 2-year follow-up of40 cases. Ann Trop Med Parasitol 87: 241- case report. J Jpn Surg Assoc 61: 2434-2438, 2000 (in Japanese, Abstract 246, 1993. in English).

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