å¡ REVIEW ARTICLE å¡

The Current Status of Parasitic Diseases in Japan Fukumi NAKAMURA-UCHIYAMA,Kenji HiROMATSU, Kenji ISHIWATA, Yukiko Sakamoto and Yukifumi Nawa

Abstract tively. Some other helminthes that cause serious diseases such as , domestic malaria and lymphatic In Japan parasitic diseases have been considered to be filaria were also successfully eradicated by the middle of successfully controlled in the last 30 years. However, 1980s (1). Such successful eradication/control of parasitic some parasitic diseases, such as food-borne zoonoses diseases resulted in the termination of the Parasite Control and/or larva migrans, are emerging and/or re-emerging Law in 1994 (1). Although the new Infectious Diseases in Japan. Furthermore, imported parasitic diseases like Control Law was applied in 1999, only five parasitic dis- malaria are also gradually increasing. Unfortunately ac- eases, four protozoan diseases (amebiasis, cryptosporidiosis, curate numbersof parasitic diseases other than echino- giardiasis and malaria) and one , echino- coccosis, malaria, amebiasis, giardiasis, or cryptospori- coccosis are assigned as the notifiable parasitoses. Nownot diosis are obscure in Japan because of the lack of a legal only the public but also medical professionals tend to con- registration system. Since symptoms and diagnostic im- sider parasitoses as a disease of the past. However,the num- aging patterns of parasitic diseases are non-specific and ber of patients having parasitic diseases referred to and have similarities with other infectious diseases or cancer, diagnosed in our laboratory has been increasing every year parasitic diseases are sometimes overlooked or left misdi- (Fig. 1A) (2, 3). In agreement with our experience, Arizono agnosed. In this review, the current status of parasitic has recently reported that morethan 1,000 case reports of diseases in Japan is briefly summarized based on the parasitic diseases were found in the database, Igaku-Chuo- analysis of the accumulated cases seen in our department. Zasshi (Japana Centra Revuo Medicina) between 1995 and Wealso outline the clinical features, differential diagno- 1999 (4). In this review, we summarize the current status of sis and treatment of representative parasitic diseases for parasitic diseases in Japan together with clinical features, di- the better understanding and managementof the para- agnosis and treatment of clinically important and frequently sitic diseases in Japan. (Internal Medicine 42: 222-236, 2003) experienced parasitoses.

Key words: food-borne zoonoses, emerging/re-emerging Current Status of Parasitic Diseases in Japan diseases, larva migrans, imported parasitoses, It is difficult to grasp the concrete number of parasitic dis- differential diagnosis, orphan drugs eases, especially those of helminthiases in Japan due to the changeover of legislation for infectious diseases. Weimple- mented the immuno-serological tests for diagnosis of para- sitic diseases in 1986. Multiple-dot ELISA method (Fig. IB), Have Parasitic Diseases Really Been which was introduced in 1991 for the primary screening to Eradicated in Japan? detect parasite-specific antibodies, has enabled us to respond faster than before to the attending physicians. The numberof In the immediate post-World War II period, Japan was re- samples referred to our laboratory has drastically increased garded as "Paradise of Parasites" because of spreading of since 1995, and reached over 400 new samples and 200 sam- soil-transmitted parasitoses such as , ples for follow-up per year in 2000 and 2001. Amongthose and hookwoomdisease. After a nationwide campaign, mass consultations, about 40%of patients were diagnosed as hav- screening, treatment and prevention of parasitic diseases ing parasitoses (Fig. 1A). The incidence of each parasitic dis- under the Parasite Control Law, the egg detection rates of ease referred to and diagnosed in our laboratory is Ascaris and hookwormin stool examination decreased from summarized in Table 1. 59.6% and 4.5% in 1950 to <0.1% and 0% in 1980s, respec- The majority of cases diagnosed in our laboratory are

From Department of Parasitology, Miyazaki Medical College, Miyazaki Reprint requests should be addressed to Dr. Yukifumi Nawa, Department of Parasitology, Miyazaki Medical College, Kiyotake, Miyazaki 889-1692

222 Internal Medicine Vol. 42, No. 3 (March 2003) Parasitic Diseases in Japan

500 Table 1. Incidence of Various Parasitic Diseases Diag- å¡ nosed in Our Laboratory during 1999-2001 1 400

Protozoa Giardiasis 3

Entoamebiasis 5 Malaria 300 99 Fascioliasis 10 4 200 Schistosomiasis 1 Metagonimiasis 1 3 100 1 Diplogonoporiasis 2 Taeniasis saginata 2 llll å y '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '99 '00 '01 i Year

A Nematoda Ascariasis lumbricoides 16 Hookwormdisease (human origin) 3 Trichuriasis 3 Multiple-dot ELISATest for Parasitic Diseases Enterobiasis 2 I 1 Lymphatic 9 NHS NHS A n g io str o n g y lia s is 7 Di Pw Di Pw A . s u u m - 1 T . c a n i s - V L M 17 0 Tc Pm Tc Pm A n isa k ia sis 1 9 G n a th o sto m ia s is 4 2 As Fh As I Fh 蝣I I S I S p i r u r o i d l a r v a m i g r a n s 3 Asx 蝣 Cs Asx M l Cs II H o o k w o r m d i s e a s e ( a n i m a l o r i g i n ) 9 i Gd L Se D ir o fila ria sis 1 0 Gd [蝣I Se li 蝣 Sr Cc Sr m蝣 Cc Others Tick bite Myasis Serum Pleural Effusion

B Scabies

Bold-face: Food-borne zoonoses, | : Larva migrans. Figure 1. Number of cases referred to our laboratory (A) and multiple-dot ELISA for parasitic diseases (B). Recently about 40% of the cases were diagnosed as having parasitoses area of this disease (5). Meanwhile A. suum-VLM is an (A). The patient's serum and pleural effusion showed a high titer of IgG against with some emerging disease in this area probably due to recent concen- cross-reactions to other trematode antigens (B). Pw: P. tration of cattle, pig and poultry farms in southern Kyushu westermani, Pm: P. miyazakii, Fh: , Cs: (6). Although imported parasitic diseases are rather rare in , Se: Spirometra erinaceieuropaei, Cc: our data, weencountered somepatients assumedto be in- Cysticercus cellulosae, Di: Dirofilaria immitis, Tc: Toxocara fected during traveling overseas, such as giardiasis, malaria, cards, As: Ascaris suum, Asx: simplex, Gd: cysticercosis and creeping eruption due to percutaneous in- doloresi, Sr: Strongyloides ratti. (b: Reprinted fection with larval dog hookworm. It should also be pointed from Clinics in Chest Medicine, 23, Nakamura-Uchiyama F out that classical soil-transmitted parasites are still present to et al, "Paragonimiasis: A Japanese perspective", 409-420, cause diseases in Japan. Copyright 2002, with permission from Elsevier Science). In contrast to our data, protozoan diseases accounted for about 45%of total case reports of parasitoses from an analy- sis of the Japanese database, Igaku-Chuo-Zasshi, during food-borne helminthiasis, especially of zoonotic nature and/ 1995 and 1999 (Table 2) (4). All patients with malaria were or larva migrans as indicated in Table 1. Among them, infected during travel in tropical and subtropical countries. Ascaris suum-YLM() and paragoni- However, patients with other protozoan diseases seemed to miasis are the two foremost parasitic diseases. The majority be infected in Japan. In fact, amebiasis is currently epidemic of these cases were from Kyushu(2). Paragonimiasis is a re- in male homosexuals and institutionalized people; few cases emerging disease in Kyushu a previously heavily endemic are imported (7). Twowater-borne outbreaks of cryptospori-

Internal Medicine Vol. 42, No. 3 (March 2003) 223 Nakamura-Uchiyama et al

Table 2. Numbersof Parasitic Diseases Case Reports in Japan Found in Japana Centra Revuo Medicina Database (1995-1999) (4)

Pr ot oz o a T re m a to d a C e sto id e a N e m a to d a

E n to a m o e h a 16 7 S c h is to sn m a 9 0 D ip h yl lo b ot h ri u m 6 2 An is aki s 9 9 P ne u mo c y s ti s 15 4 P a ra g o n im u s 4 9 S p a rg a n u m 3 1 D irofila ria 5 4 T o x o p l a sm a 10 2 C lo n o rc h is 1 6 T a e n ia s o liu m 2 7 A s c a r is 5 2 P la s m o d iu m 9 4 F a sc io la 1 3 E c h in o c o c c u s 2 1 St ron g yl o id es 4 8 A c a n t h a m o e b a 3 5 T a en ia s a g in a ta 6 T ox o ca r a 2 7 G ia rd ia 1 4 D ip lo g o n o p o ru s 5 G n a th o stn m a 2 3 L e is h m a n ia 1 3 Sp iru rina 19 A m e b ic e n c ep h a litis 1 0 A s c a r is su u m 16 Iso sp o ra 6 H o o k w o r m s l l T r ic h o m o n a s 6 E n te r o b iu s 10 C ry p t os po r i di um 5 A ng i os tr on gy lu s 8 Trich u ris 8 蝣 Trich ine lla 5

T o ta l 6 0 6 1 5 5 1 5 2 3 9 3

diosis are still fresh in our mind (8, 9). Cryptosporidium (17-19). oocysts and Giardia cysts were detected in raw and even in The increase in numberof imported parasitoses such as filtrated water in Japan (10). Amongthe helminthiases in this malaria and giardiasis is directly related to the increasing database, most are food-borne zoonoses and/or larva numberof overseas travelers. Howeverforeign foods con- migrans, as seen in our data. It should be emphasized again taminated by parasites are also imported in Japan. Recently, that classical parasites such as Ascaris and hookwormcon- we encountered paragonimiasis cases amongforeigners liv- tinue to exist at a low level in Japan. ing in Japan. The sources of their infection were imported Oneof the notable findings from the analyses of our data Chinese crabs served in a Chinese restaurant or bottled and the literature survey from the databases is that the major- drunken (liquor-soaked) crabs brought out from China as a ity of helminthiasis is food-borne zoonoses. This trend may souvenir (20). Food-borne outbreaks associated with para- be reflecting preferential food-habits of the Japanese con- sites have been reported in the world (21). Wemaybe seeing suming raw materials as "Sushi" or "Sashimi" with "Soy more patients with food-borne parasitic diseases in Japan sauce". For example anisakiasis and diphyllobothriasis are with the increment of food trading and the popularization of highly prevalent in Japan. Creeping eruption and acute abdo- ethnic dishes. mendue to Spirurina Type X larvae infection after eating In summary,parasitic diseases currently seen in Japan are small scintillant squids has recently emerged (ll). In addi- characterized as follows: tion to marine , crustaceans and shellfishes, freshwater 1) Food-borne diseases and/or larva migrans related to fishes and wild animal meat are also served as "Sushi" or Japanese food-habits: anisakiasis, diphyllobothriasis, "Sashimi". In this aspect, it is interesting that more than 70% , sparganosis and other diseases. of the recent paragonimiasis cases were coming from eating 2) Emerging/Re-emerging diseases: cryptosporidiosis, echi- raw wild boar meat, though freshwater crabs have been con- nococcosis, spiruroid larva migrans, A. suum-YLM, sidered the important source of Paragonimus infection (5). paragonimiasis and other diseases. The major source of Gnathostomasp. infection is freshwater 3) Gradually increasing imported parasitoses: malaria, giar- fishes such as brook trout, imported loach or snakehead diasis and cysticercosis. (12). In addition, snakes are also important reservoir hosts of 4) Persistent occurrence of classical soil-transmitted para- G. doloresi as well as Spirometra erinaceieuropaei (13, 14). sitoses: ascariasis lumbricoides, hookworm and other dis- Some gnathostomiasis and sparganosis patients were in- eases. fected by eating snakes as "Sashimi", since they believed in tonic effects of raw snake meat (15). Chicken/cattle liver is an important source for infection with A. suum- and Clinical Features of Parasitoses: Symptoms, -YLM in middle-aged men (16). Related to Diagnosis and Treatment this, some Japanese ingest actively raw materials as medi- In the analysis of the current trends of parasitic diseases in cine. For example, freshwater crab juice given for asthma Japan, wehave noticed that a few malaria patients are still treatment caused paragonimiasis, and ingestion of raw slugs dying almost every year because of delayed and/or inade- for treatment of lumbago or mineral supplement caused quate diagnosis (22). Furthermore, parasitic zoonoses are

224 Internal Medicine Vol. 42, No. 3 (March 2003) Parasitic Diseases in Japan

Table 3. Clinical Symptomsand Possible Parasitoses, Diagnosis and Treatment 1 . F ev e r

P o s s i b l e p a r a s i t o s e s F i n d i n g s R e m a r k s D i a g n o s i s T r e a t m e n t

T ra v el a b ro ad M a la r ia A n e m ia B lo o d sm e ar V ary 3 K id n ey failu re /C N S in v o lv em en t

2 . A b d o m in a l sy m p to m - D ia rr h e a

P o s s i b l e p a r a s i t o s e s F i n d i n g s R e m a r k s D i a g n o s i s T r e a t m e n t

. ,.. MucousandbloodystoolEntoamebiasis _ __y JLoosepassage/Waterystool sc tT-tD^ , tI m m u n o da e cfi ci蝣 en c yJ /((THtTrTIo^Vp7hx)o zoiteSs. )to (o1,l0e00xmag/m. d^aiynfaortilOodna ys)M N Z

MNZ Giardiasis Travel abroad, Water supply Stool examination Ingestion of imported fruits (cysts) (750 mg/day for 7-10 days) Stool examination Cryptosporidiosis Immunodeficiency (HIV) Symptomatic treatment (oocysts)

Immunodeficiency (ATL, HIV) Stool examination TBZ Strongyloidiasis (larvae) (30-50 mg/kg/day for 3 days) Origin/Habitat (Okinawa) Immunodiagnosis IVM (A dose of 200 ^ig/kg at once) à"Loose passage/Watery/Fatty stool Metagonimiasis Ingestion of freshwater fish PZQ "Ayu" (50 mg/kg/day for 1-2 days)

Ascariasis PP Ingestion of organic vegetables Stool examination (A single dose of 5-10 mg/kg) Hookworminfection (eggs)b

PZQC Tapeworm Ingestion of marine fish, beef or (10 mg/kg at one time) pork +Laxative

3. Abdominal symptom-Acute abdomen Possible parasitoses Finding s Remarks Diagnosis Treatment Anisakiasis (Stomach) Endoscopically Pick out Anisakiasis Ingestion of marine fish and squid (Small intestine) X-p: Ileus åImmunodiagnosis Symptomatic treatment c . . , , (Eosinophilia) Spiruroid larva F Ingestion of small scintillated migrans squids A scariasis Ingestion of organic vegetables E ndoscopically Pick out (ectopic migration) 4. Liver or biliary tract lesions

Possible parasitoses Finding s R em arks D iagnosis Tre atment

STD Immunodiagnosis Amebiasis US, CT, MR: liver abscess with clear Immunodeficiency (HIV) Detection of MNZ irregular margin Not always including the intesti- trophozoites in ab- (1,500 mg/day for 10 days) nal lesion scess drainage

Immunodiagnosis TCBZ US, CT, MR: SOL with irregular margin Ingestion of herb or cattle liver Fascioliasis (>3-4 cm) Cattle farmer (Detection of (A dose of 10 mg/kg at once) Eosinophilia eggs)

Internal Medicine Vol. 42, No. 3 (March 2003) 225 Nakamura-Uchiyama et al

(Table 3. continued)

US: Beads sign Ingestion of chicken/cattle liver A. suum-IT. canis- CT, MR: Small multiple nodule (0.5-1.0 ABZ or organic vegetables (10-15 mg/kg/day for 4-8 VLM cm) History of dog parenting weeks) Eo sinophilia Lung/Ocular/CNS involvements

Surgical resection US, CT, MR: Poly cystic SOL with ir- Origin/Habitat E. multilocularis: Hokkaido Immunodiagnosis ABZ Echinococcosis regular margin E. granulosus: Manchuria (Repeated administration of C alcification CNS (/Lung) involvements 10-15 mg/kg/day for 4 weeks)

Ingestion of freshwater crabs or Paragonimiasis Hepatic capsulitis, Calcification PZQ (Eo sinophilia) wild bore (75 mg/kg/day for 3 days) Lung/Skin/CNS involvements 5. Respiratory symptomsor lesions Possible parasitoses Findings Remarks Diagnosis Tre atme nt Ingestion of freshwater crabs or X-p, CT: Vary (Pleurisy or parenchymal Immunodiagnosis PZQ Paragonimiasis lesions ) wild bore Eo sinophilia Skin/CNS involvements (Egg detection) (75 mg/kg/day for 3 days)

Loffler Syndrome Ingestion of organic vegetables Detection of lar- ABZ Ascariasis X-p, CT: Diffuse mottled infiltration vae in sputum (10-15 mg/kg/day for 3 days) Hookwormdisease (resemble military tuberculosis or viral Immunodiagno si s TBZ Strongyloidiasis pneumonia) Origin/Habitat (Okinawa) (30-50 mg/kg/day for 3 days) Eo sinophilia Immunodeficiency (HIV, ATL) IVM (A single dose of 200 ng/kg)

Ingestion of chicken/cattle liver A. suum-IT. canis- ABZ X-p, CT: Diffuse mottled infiltration or organic vegetables (10-15 mg/kg/day for 4-8 VLM Eosinophilia History of dog parenting Liver/Ocular/CNS involvements weeks) Immnunodiagnosi sd X-p, CT: Single nodular lesion (coin lesion) DEC (Eosinophilia) (6 mg/kg/day for 2-4 weeks)

6. Skin lesions

Possible parasitoses Findings Remarks Diagnosis Treatment Surgical resection ABZ Eosinophilia (-) infectionDog hookworm Travel abroad (Resort beach) Biopsy (10-15 mg/kg/day for 3 days) IVM Creeping eruption (A dose of 200 ng/kg at once) Spiruroid larva Ingestion of small scintillated Surgical resection migrans squids

Ingestion of freshwater fish or Surgical resection Gnathostomiasis snakes ABZ (10-15 mg/kg/day for 3 days) Eo sinophilia Immunodiagnosis Biopsy Ingestion of chicken, snake or Surgical resection6 Mobile nodular Sparganosis frog PZQ lesion (75 mg/kg/day for 3 days)

Paragonimiasis Ingestion of freshwater crabs or PZQ wild bore (75 mg/kg/day for 3 days)

226 Internal Medicine Vol. 42, No. 3 (March 2003) Parasitic Diseases in Japan

(Table 3. continued)

7. CNS symptoms

Possible parasitoses Finding s Remarks Diagnosis Treatment Ingestion of snails or slugs Angiostrongyliasis Eosinophilia (blood, CSF) Ingestion of vegetables contami- Symptomatic treatment Meningitis nated by infectious mollusean X-p, CT: Soap bubble sign (chronic) Ingestion of freshwater crabs or PZQ Paragonimiasis åCalcification appeared soli- wild bore (75 mg/kg/day for 3 days) tary round cystic, oval cystic Eosinophilia (blood, CSF) à"Immunodiagnosis Ingestion of food or water conta- ABZ minated by T. solium eggs (10 mg/kg/day for 4 weeks) Cysticercosis CT, MRI: vary Ingestion of uncooked pork PZQf depending on the stage of dis- Travel abroad (50 mg/kg/day for 2 weeks) ease Adult wormin intestine +Steroid (cyst with/without edema, nodule, calcification) Origin/Habitat Echinococcosis Encepha- (Hokkaido) Surgical resection litis Liver (/Lung) involvement

Immunodiagnosis MNZ Amebiasis CT, MRI: single or multiple STD, Immunodeficiency (HIV) enhancing lesions Liver involvement DNAdiagnosis (1,500 mg/day for 10 days)

Travel abroad Malaria Sudden onset Anemia Blood smear Quinine etc Kidney failure

CT, MRI: Multiple nodular Immunodeficiency (HIV) lesions Ingestion of uncooked chicken/ Immunodiagnosis Pyrimethamin Toxoplasmosis (ring enhancement with thin pork DNAdiagnosis S ulfamonomethoxine and smooth wall) History of parenting Ingestion of chicken/cattle liver ABZ A. suum-IT. canis- Myeliti s CT, MRI: small nodular le- or organic vegetables (10-15 mg/kg/day for 4-8 VLM Immunodiagnosis sions reflecting inflammation History of dog parenting weeks) Lung/Liver involvement

"Depending on the patient's state, drug resistance malaria. bIn case of tapeworm infection, most patients have an episode of release of wormsegments (proglottids). cIn case of (pork tapeworm) infection, elimination by "Gastrographin" is better for preventing autoinfection. dIn case of inactive dirofilariasis, immimodiagnosis is not always useful. eIt is important to excise the entire parasites. fWhenthe adult wormexists in small intestine, worm expulsion by "Gastrographin" should be prior to PZQ treatment for preventing the autoinfection. MNZ: metronidazole, TBZ: thiabendazole, IVM: ivermectin, PZQ: , PP: pyrantel pamoate, TCBZ: triclabendazole, ABZ: albendazole, DEC: diethylcarbamazine. often misdiagnosed as malignant diseases resulting in exces- falciparum infection called malignant malaria progresses sive diagnostic tests or unnecessary surgery (2). These facts rapidly and shows a high mortality rate within a week or so. remind of us the vital importance of the correct diagnosis for Since red blood cells infected with P. falciparum tend to parasitic diseases. Therefore we outlined the clinical features cause obstruction in small vessels of and kidney, the and tips for diagnosis and treatment of representative para- patient show acute cerebral symptomsor renal failure (22). sitic diseases in Japan to facilitate a better understanding of It should be noted that the fever pattern is not always typical the parasitic diseases for correct diagnosis and moreappro- even in the patients infected with P. vivax or P. malariae. It priate treatments (Table 3). is important for the diagnosis of malaria to detect the malaria parasite in blood smear by Giemsa staining (pH 7.2) (Fig. 2). Fever Whenfluorescence microscopy is available, rapid diagnosis Whenpatients with FUO(fever of unknown origin) have of malaria can be obtained by acridine orange staining (24). a history of traveling abroad especially to tropical develop- Quinine and sulfadoxine/pyrimethamine are the commer- ing countries, we have to think of the possibility of malaria, cially available anti-malarial drugs in Japan. However,the dengue fever or typhoid fever (23). Particularly Plasmodium first choice of drugs depends on the patient's state. A combi-

Internal Medicine Vol. 42, No. 3 (March 2003) 227 Nakamura-Uchiyama et al

Table 4. Orphan Drug List Available from the Japan Health Science Foundation Orphan Drug Study Group Under Approval of Ministry of Health, Labor and Welfare3 Dr ug Fo rm ul a In di c at io n C hloroquine sulfate Tablet M alaria A tovaquone/Proguanil Tablet M alaria ,å *>-:* A rtesunate Tablet/Suppository M alaria Quinine glyconate Inj ectable Malaria Primaquine phosphate Tablet Malaria Metronidazole Inj ectable Entoamebiasis D iloxanide furoate Tablet E ntoam ebiasis Sodium stibogluconate Injectable Leishmaniasis Iverm ectin Tablet O nchocerciasis (Strongyloidiasis) Figure 2. Direct demonstration of P. falcipalum in blood Scabies smear (arrowhead, Giemsa staining, pH 7.2). Triclabendazole Tablet Fascioliasis Paragonim iasis Ribavirin Tab let Viral He morrhagic nation of drugs having different pharmacological actions or Fever having targeting the different of malaria parasite stages is Surami n Inj ec table Trypa nosomias is necessary for complete cure. In addition drug-resistant ma- Melasoprol Inj ectable Trypanosomiasis laria parasite are gradually increasing in almost all endemic Eflornithine Inj ectable Trypanosomiasis areas (22). Various anti-malarial drugs are available from the Japan Health Science Foundation Orphan Drug Study Group aFor dosage and administration refer to Study Group website under approval of Ministry of Health, Labor and Welfare (http ://www.ims.u-tokyo. ac.jp/didai/orphan/index.html). (Table 4). Detailed information such as dosage and admini- stration or pharmacological actions of drugs are available in the Study Group website (http://www.ims.u-tokyo.ac.jp/ Cryptosporidiumdrugs is urgently needed (29). In case of didai/orphan/index. html ). severe intestinal entoamebiasis with peritonitis, metroni- dazole (MNZ)div is available from the Orphan Drug Study Abdominal symptom: Group. Someparasitic infections cause diarrhea as seen in Table 3.2. Mucousand bloody stool is characteristic of intestinal Abdominalsymptom:acute abdomen entoamebiasis. Massive infection with Metagonimusor Someparasitic diseases cause acute abdomen(Table 3.3). giardiasis, cryptosporidiosis and strongyloidiasis in immuno- Amongthem, gastric anisakiasis is probably the most preva- compromisedhosts maypresent severe diarrhea leading to lent one. Typical anisakiasis develops 5-6 hours after the in- protein-loosing enteropathy (23, 25). Therefore when a pa- gestion of marinefish, mackerelsor squids. Principle of tient with severe diarrhea due to infection with opportunistic diagnosis and treatment of this disease is to pick out the parasites is found, it is important to search for the underlying wormsendoscopically (30). In the case of intestinal disease leading immunodeficiency. Definitive diagnosis can anisakiasis, patients maypresent ileus. Recently, Spirurina be obtained by direct demonstration of parasite trophozoites, TypeX larva infection has been emergedand patients de- cysts, oocysts, larva or eggs in feces. velopileus and/or creepingeruption(1 1). Themajorsource Thiabendazole (TBZ) was the only approved therapeutic of infection withSpirurina TypeXlarva is small schintillant drug for strongyloidiasis in Japan. This drug usually requires squids. Special anthelminthic drugs are not found for at least a 3-day dosage but has a high frequency of side ef- Anisakisor Spirurina,andspontaneouscureof these diseases fects which interfere with compliance (26, 27). Instead of is often observedbyconservativetreatmentalone. Therefore TBZ, ivermectin (IVM), a newly developed anti-Strongy- whenthe patient withacute abdomenis strongly suspectedof loides drug, is now commercially available. This drug is sig- having these parasitic infections based on the eating history, nificantly effective with a single dose of 200 |ug/kg without excessive examination or unnecessary surgery should be severe side effects (28). Standard treatment protocol for avoided. cryptosporidiosis in patients with HIVhas not been estab- Asan extremelyrare case, colonicileuses dueto nodular lished yet. Although there are a few reports suggesting that lesions causedby Gnathostomamigration wasreported pre- azithromycin, clarithromycin or roxithromycin were effec- viously (31). Acuteabdomendue to ectopic migrationto the tive for cryptosporidiosis in patients with HIV, the efficacy bile duct or pancreatic duct of Ascarislumbricoidesare often of these drugs are still controversial and reports of ineffec- reported, suggestingthat this classic parasite still exists spo- tive cases exist. Thus, the development of effective anti- radically in Japan (4). Massive infections with A. lumbri-

228 Internal Medicine Vol. 42, No. 3 (March 2003) Parasitic Diseases in Japan

Figure 3. Liver lesions in various parasitic diseases. These findings are similar to those of hepatocellular car- cinoma, cholangiocellular carcinoma or metastatic tumor; Abdominal CTof fascioliasis (A), A. suum-YLM (B), abdominal echo and CT of echinococcosis granulose (C, D) and CT of entoamebiasis (E). E. histolytica trophozite in liver abscess drainage (F). coides cause bolus obstruction in the intestine (32). occupying lesions and misdiagnosed as malignant diseases such as hepatocellular carcinoma, cholangiocellular carci- Abdominal symptom: lesions in the liver or biliary nomaor metastatic tumor because of similarity on diagnostic tract imaging (Fig. 3). Fascioliasis and A. suum-IT. canis-VLM The liver and biliary tract are involved in some parasitic are frequently associated with peripheral blood eosinophilia. diseases (Table 3.4). Bile duct is the target of Fasciola and Thus clinicians should be aware of the possibility of parasitic Clonorchis. Ascaris, Toxocara and hookwormlarvae are car- diseases especially when patients with liver lesions reveal ried into liver via portal blood stream. Notably these liver- eosinophilia. Immunodiagnostic methods such as multiple- affecting parasitic diseases are often manifested as space dot ELISAto detect antibody against parasites are particu-

Internal Medicine Vol. 42, No. 3 (March 2003) 229 Nakamura-Uchiyama et al lary valuable for the rapid screening to diagnose these dis- juvenile worms migrate from the small intestine to the lung eases (33). through several tissue/organs including peritoneal organs. Fascioliasis cases in Japan have been found mostly around Thus, the liver, peritoneal cavity, abdominal skin, or small-scale cattle farms. Over 100 cases were found by 1992 urogenital organs are occasionally affected (45). Most of (34) and more cases have been added year after year (35, these patients having ectopic infection are asymptomatic and 36). Praziquantel (PZQ) is the only available drug for che- found by chance in a post-operative histopathological exami- motherapy for fascioliasis. However, the efficacy of PZQfor nation under the diagnosis of non- (46, 47). fascioliasis remains controversial, in spite of its broad In patients with active ectopic paragonimiasis, immuno- trematodicidal spectrum (36). Recently, triclabendazole diagnosis is useful and, regardless of the site affected, pa- (TCBZ) is recommended by WHOas an essential drug tients can be cured by PZQ.Recently we encountered a case against fascioliasis (37), and TCBZtablets for human use of active hepatic capsulitis due to infection with P. have become available since April 2001 through the Orphan westermani (48). Drug Study Group (38). Schistosomiasis japonicum and clonorchiasis are well Larva migrans due to infection with T. canis is famous for known causes of liver cirrhosis, which sometimes becomes its preferential ocular involvement in children in Western liver cancer. Once liver cirrhosis has developed, anthel- countries. The major route of infection is thought to be a di- minthic treatment is ineffective. Therefore, early diagnosis rect oral infection from pet puppies. However in Japan the and treatment is essential for these diseases. Nonew cases of number of adult patients is far greater than that of children schistosomiasis and few cases of clonorchiasis have been re- (16). Similarly the majority of A. suum-VLMpatients in ported in Japan. However, it should be noted that these dis- Japan are middle-aged males. In Japan, both Toxocara-VLM eases still exist all over the world especially in Asian and A. suum-YLMare thought to occur mainly by ingesting countries and a few imported cases have been reported. chicken/cattle liver or organic vegetables contaminated by parasite eggs (16). Because of the nature of migration of A. Respiratory symptomsor lesions suum and T. canis larvae, the liver (Fig. 3B) and lungs (Fig. Possible parasitic diseases presenting respiratory symp- 4E) are the commonest sites affected in A. suum-IT. canis- toms or lesions are summarized in Table 3.5. Paragonimiasis VLM(39, 40). It should be noted thatA. suum as well as T. patients often present respiratory symptoms with eosino- canis migrate occasionally into the CNS(41). Standard pro- philia. Since radio-imaging appearances of paragonimiasis tocol for chemotherapy on VLMhas not yet determined. are variable, it is difficult to distinguish this disease from Albendazole (ABZ) is assumed to be effective for VLM,but lung cancer, tuberculosis, or fungal infections (Fig. 4A-D) needs 4-8 weeks of continuous administration and has side (45). It should be noted that despite remarkable chest radio- effects causing transient liver dysfunction. logical findings in the lung parenchyma and/or pleural cav- Echinococcosis is a slowly progressive and chronic dis- ity, about 20% of paragonimiasis patients are asymptomatic; ease caused by infection with Echinococcus multilocularis or the presence of lung lesion happens to be discovered by E. granulosus. The former infection to humans is often lethal chest X-ray examination at a regular health screening (45). because of its metastatic nature and is emerging in Hokkaido Recently, we demonstrated that pleurisy with a high degree (42). Whereas the latter infection is benign and only a few of eosinophilia (>20%) is characteristic of the early stage of cases were sporadically found in Japan (Fig. 3C, D) (43). paragonimiasis, whereas parenchymatous lesions with rela- Though the diagnosis can be achieved by the serological test tively low eosinophilia (- 10%) were characteristic of the late and findings on ultrasonography, habitat profile of the pa- stage (49). Immunodiagnosis is quite useful for the diagnosis tient is the most important information to suspect of of paragonimiasis because egg detection rates in sputum or echinococcosis (44). Surgical resection is the only way to bronchoscopic aspirates were less than 50%(45). In the very treat echinococcosis. Benzimidazole derivatives such as early stage of this disease, detection of parasite-specific IgM ABZor mebendazole (MBZ)seem to be effective, however rather than IgG antibody is useful and should be considered it is difficult to obtain complete cure (44). Thus early diagno- (49). Pulmonary paragonimiasis can be treated by oral ad- sis and subsequent surgical treatment is essential to cure this ministration of PZQ (75 mg/kg/day for 3 days) with an al- disease. most 100% cure rate (45). Entoamebiasis is emerging in Japan, especially as STD. A. lumbricoides, hookwormand Strongyloides infection Though the parasite primarily causes colitis (amebic dysen- cause Loffler's syndrome, an acute eosinophilic pneumonia tery), abscess in the liver (Fig. 3E) is not rare. Amebic liver with tracheitis. Pathogenesis of this syndrome is thought to abscess is diagnosed directly by a demonstration of be due to hypersensitive reaction to migrating larvae. Severe trophozoites in the drainage fluid from the abscess (Fig. 3F) symptoms such as cough, wheezing and dyspnea last for 7- or indirectly by immunodiagnostic methods (33). Intestinal 10 days and usually resolve spontaneously when larvae mi- involvement is not always evident. MNZis a drug of choice. grate out of the lungs (50). Whenthe disease status is wors- In severe cases, MNZdiv is available from the Orphan Drug ening rapidly or patients showthe signs of septicemia and/or Study Group. CNSinvolvement, we should consider the possibility of dis- Although Paragonimus is a lung-seeking trematode, its seminated strongyloidiasis in which drastic increase in

230 Internal Medicine Vol. 42, No. 3 (March 2003) Parasitic Diseases in Japan

Figure 4. Lung lesions in various parasitic diseases. Variance of paragonimiasis on chest radiography; nodu- lar (A), mixed pattern (B), pleural effusion and pneumothrax (C, D). Chest CT findings of A. suum~YLM(E) and dirofilariasis (F). (A-D: Reprinted from Clinics in Chest Medicine, 23, Nakamura-Uchiyama F et al, "Paragonimiasis: A Japanese perspective", 409-420, Copyright 2002, with permission from Elsevier Science). numberof Strongyloides larvae occurs from autoinfection as- ratory symptoms, lesions maybe seen not only in the lungs sociated with the invasion of intestinal bacteria. Larvae can (Fig. 4E) but also in the liver, eyes and CNS. As the nature be seen in the sputumsmear of disseminated strongyloidiasis of ascarid larvae, they migrate first into the liver via portal patients. Such a condition is frequently seen in patients with blood flow, then migrate into lungs via blood stream, and immunodeficiency (51). Whenever we see disseminated then disseminated by systemic circulation. Thus it is impor- strongyloidiasis patients in Japan, we must consider the pos- tant to perform systematic examinations of all possible or- sibility of ATL/HTLV- 1 infection. gans affected in patients with A. suum-IT. canis-VLM (16). In cases of A. suum-IT. canis-YIM presented with respi- Treatment for VLMhas been described in the liver lesion

Internal Medicine Vol. 42, No. 3 (March 2003) 231 Nakamura-Uchiyama et al

Bi

D -* à"*. å c[

Figure 5. Skin lesions. Creeping eruption due to infection with Gnathostoma (A) and larval dog hookworm (C). Gnathostoma exists in deep site (B, x25) whereas larval hookworm is in the epidermis (D, x200). section above.filariasis successfully diagnosed with serological tests (52). Dirofilaria immitis is known as a zoonotic parasite caus- Diethylcarbamadine (DEC) is a recommended drug for pul- ing pulmonary dirofilariasis in humans. Typical dirofilariasis monary dirofilariasis, though it is ineffective for chronic is asymptomatic and characteristic of coin lesion in the chest cases. radiography (Fig. 4F). Therefore, patients with pulmonary As extremely rare cases, various parasites such as dirofilariasis have been often misdiagnosed as malignancy Gnathostoma (53), Spirometra (54, 55) and Anisakis (56) un- and received unnecessary examinations and/or surgical treat- expectedly migrate into the pleural cavity causing pleuro- ments. We have reported three cases of pulmonary diro- pulmonary lesions. All of these cases were serologically

232 Internal Medicine Vol. 42, No. 3 (March 2003) Parasitic Diseases in Japan

;*S

umiå rI

Figure 6. CNSlesions in various parasitic diseases. Various lesions of neurocysticercosis depending on the stage of the diseases (A, B). MRIfindings of spinal lesion of A. suum-YLM(C). (B: Reprinted from Rinsho Shinkeigaku, 42, Nakajima Met al, "A case of neurocysticercosis suggestive of a reinfection, 20 years after the initial onset", 18-23, 2002, with permission from Japanese Society of Neurology. C: Reprinted from J Neurol Neurosurg Psychiatry, 70, OsoegawaMet al, "Localised myelitis caused by visceral larva migrans due to Ascaris suum masquerading as an iso- lated tumor", 265-266, 2001, with permission from BMJ publishing Group). diagnosed. In cases of pulmonary sparganosis (Sparganum loach and snakehead fish) or snakes (12, 13, 15) and presents mansoni, larval form of S. erinaceieuropaei, infection), PZQ both types of lesions depending on its species (58). treatment at the dose of 75 mg/kg/day for 3 days is highly ef- Sparganosis due to infection with the S. mansoni, larval form fective. At the present, standard protocol for pleuro- of S. erinaceieuropaei, occurs by ingestion of raw or under- pulmonary nematodiasis due to ectopic migration of cooked chicken, snake or frog meat and presents with a Gnathostomaor Anisakis larvae has not been established yet. slowly moving nodular lesion (14). Skin involvement is well Symptomatolytic treatment with anti-inflammatory drugs is known in paragonimiasis (45). Spirurina Type X larvae were the only practical way to treat these patients. identified to cause creeping eruption moreoften than ileus (ll). Recently we reported 7 cases of creeping eruption due Mobile skin lesions to infection with dog hookworm larvae overseas (Fig. 5C, D) Mobile skin lesions strongly suggest the presence of para- (59). As can be seen in those pictures, creeping eruption due sitic infection, and causative parasites can be predicted, to dog hookwormlarvae is usually limited to the epidermal though not definitely, from the type of skin lesions (creeping layer. eruption or mobile nodular lesion) and the eating history The surgical removal of the larva is the best way for treat- (Table 3.6) (57). Gnathostomiasis (Fig. 5A, B) occurs by in- ment as well as leading to definitive diagnosis. Howeverthe gestion of freshwater fish (brook trout, domestic or imported rate of resection is usually low. Thus immunodignosis is im-

Internal Medicine Vol. 42, No. 3 (March 2003) 233 Nakamura-Uchiyama et al

portant for the diagnosis of these diseases (57). Several re- CNScan be treated successfully with MNZ,chemotherapy ports have documented that ABZ is effective for gna- for meningoencephalitis due to free-living amoeba like thostomiasis and larval animal (58, 59). Naegleria has not been established. Recently Wear et al (60) recommendeda single oral dose of IVM(12 rag/adult or 200 |ug/kg B.W. at once) for hookworm Conclusion: We Are Still Living infection. in This WormyWorld CNSsymptoms Fromthe global point of view, helminth infections are still Possible parasitic diseases affecting CNSare summarized threatening to humanhealth and current numbers of helminth in Table 3.7. Humaninfection with Angiostrongylus canto- infections are estimated as about 4,500 million whichnum- nensis occurs by ingesting contaminated snails and slugs, or ber is beyond Stoll's estimate in 1964 (67). Parasitic diseases green vegetables, and appears as eosinophilic menin- in Japan will remain to exist and recent rapid globalization is gitis/meningoencephalitis. Though the severity of symptoms a warning alarm us to pay more attention not only to domes- depends on wormburden, the patients maypresent cranial tic but also to the imported parasitic diseases in Japan. We nerve involvement (especially facial palsy), ocular manifes- should be aware of the possibility of parasitic diseases be- cause we are still living in this wormyworld. intationsaddition(mainlyto headachediplopia), withpsychosis,fever (61).and sensoryThis parasiteimpairmentis widely distributed in Okinawa but sporadically found around Acknowledgments: This work is supported in part by a Grant-in-Aid for the international trading harbors of main lands of Japan (62). Scientific Research KH42074from the Ministry of Health, Welfare and Somecases of Angiostrongylus infection by ingesting raw Labor. Wegive special thanks to Naoki Arizono, MD,PhD(Department of slugs as medical treatment have been reported (18, 19). Medical Zoology, Kyoto Prefectural University of Medicine) and Masahide Yoshikawa, MD, PhD (Department of Parasitology, Nara Medical Although the standard protocol has not yet been established, University) for their valuable advice for this study. Wealso thank the at- consecutive administration of ABZis reported to be effective tending physicians for providing the diagnostic imaging. The excellent tech- nical assistance of Ms Ayumi Tanaka for immunodiagnosis is gratefully for treatment of angiostrongyliasis. acknowledged. Larval form of Taenia solium, Cysticercus cellulosae, fre- quently causes cerebral, ocular, and subcutaneous cysti- cercosis (63). CT and MRIfindings of neurocysticercosis References vary depending on the stage of the disease (Fig. 6A, B) (64). Infection to humans occurs by ingestion of food or water 1) Kagei N, Hayashi S. 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in: Pathology of Infectious Diseases. Vol. 1 Helminthiases. Meyers neurocysticercosis. AmJ Roentogenol (AJR) 173: 1485-1490, 1999. WM Ed. AFIP, Washington DC, 2000: 373-384. 65) Osoegawa M, Matsumoto S, Ochi H, et al. Localised myelitis caused 62) Nishimura K. Angiostrongyliasis cantonensis. in: Progress of Medical by visceral larva migrans due to Ascaris suummasquerading as an iso- Parasitology in Japan (Japanese Edition). Vol. 7. Otsuru M, Kamegai S, lated spinal cord tumor. J Neurol Neurosurg Psychiatry 70: 265-266, Hayashi S. Eds. Meguro Parasitological Museum, Tokyo, 1999: 389- 2001. 408. 66) Sugita Y, Fujii T, Hayashi I, et al. Primary amebic meningoencephalitis 63) Neafie RC, Marty AM, Johnson LK. Taeniasis and cysticercosis. in: due to Naegleriafowled: an autopsy case in Japan. Pathol Int 49: 468- Pathology of Infectious Diseases. Vol. 1 Helminthiases. Meyers WM 470, 1999. Ed. AFIP, Washington DC, 2000: 117-136. 67) Crompton DW.Howmuch human helminthiasis is there in the world? 64) Noujaim SE, Rossi MD, Rao SK, et al. CT and MR imaging of J Parasitol 85: 397^03, 1999.

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