suspected. Urine cytology showed numerous inflammatory cells, including ..... areas endemic for cysticercosis (tissue infection with Taenia soli- um tapeworm ...
Acute and Chronic Schistosomiasis CHARLES H. KING Case Western Reserve University
or most American physicians, the mention of schistosomiasis evokes vague memories of "that parasite lecture we had in medical school." Few clinical facts are recalled. This situation is unfortunate, since estimates made by the World Health Organization indicate that more than 300 million people around the world live in an environment in which they are regularly exposed to schistosome infection. Thus, recent changes in immigration patterns, along with recent increases in recreational travel to "exotic" locations, have made it much more likely that a physician in the United States will be confronted by a case. A working understanding of the life cycle of schistosome infection and an understanding of the immunologic basis of infection-associated disease will allow rapid assessment of .the risk of schistosomiasis in a given patient. The case presentations that follow illustrate the role of clinical information in establishing the diagnosis of schistosomiasis in two quite different settings.
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Dr. King is Associate Professor of Medicine, Division of Geographic Medicine, Case Western Reserve Universify School of Medicine, Cleveland. Hospital Practice March 15, 1991
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Case 1·Presentation
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gr 20-year-old American student participated in a development project in Africa during li~r summer vacation. While there, she and other students lived in housing that lacked plumbing, and they bathed on at least one occasion in a slow-moving freshwater stream in an area endemic for Schistosoma mansoni. During the first weeks of her stay, she and several colleagues experienced an itchy papular rash on the lower legs. The rash subsided spontaneously without specific therapy, but the patient felt mild malaise and in subsequent days never felt entirely well. Five weeks later (and following her return to the United States), she began to experience severe fevers with drenching sweats, abdominal cramping, and watery diarrhea. Initial clinical evaluation favored the diagnosis of malaria, and she was treated with antimalarial drugs despite several negative blood smears. Other laboratory testing was remarkable for a peripheral eosinophilia of I 0%. Despite partial improvement in her symptoms, she continued to have high fevers, and painful swelling and arthralgia developed in the large joints of her arms and legs. On the basis of a more detailed travel history and a review of her clinical presentation, a working diagnosis of acute schistosomiasis was entertained. Stool examination for eggs of S. mansont was negative on three occasions, but serology indicated a high titer of antischistosomal antibodies. Therapy with praziquantel was complicated by exacerbation of the patient's fevers, requiring parenteral corticosteroids for control of symptoms. 1\vo weeks later, the patient's symptoms had resolved. She is currently in good health and doingwell in her college career.
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Case 2 Presentation Kenyan exchange student matriculating at a uniA 20-year-old versity in the United States was found to have moderate irondeficiency anemia, microscopic hematuria, and proteinuria on a screening physical examination. An ultrasound study of the kidneys and bladder revealed severe right-sided hydronephrosis, with a shrunken right kidney, a polypoid lesion of the bladder, and an enlarged prostate. Cancer of the lower urinary tract was strongly suspected. Urine cytology showed numerous inflammatory cells, including 5% eosinophils, with significant epithelial metaplasia but without frank neoplasia. An incidental finding of the cytologic study was a single S. haematobiilm egg. Subsequent cystoscopy revealed hyperemia, "sandy patches," small ulcerations, and a single large polyp, which on biopsy contained schistosome eggs and granulomatous inflammation but no 15. 1991
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tumor. A diagnosis of chronic urinary schistosomiasis was made. Therapy with praziquantel was well tolerated, and over a period of two months, the patient's hematuria, proteinuria, and anemia gradually resolved. Follow-up ultrasound examination 12 months after therapy showed resolution of the bladder polyp and the absence ofhydronephrosis, but a persistently small right kidney.
Etiology and Epidemiology
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chi'stosomes are parasite flukes (trematodes) that attain a length of 1 to 2 cm as adult worms and reside as adults in the venous circulation of their human host. The genus name Schistosoma, or literally "split body," derives from the cleft or groove in the male-a cleft in which the female typically lives. The most prevalent species include S. mansoni and S.japonicum, which colonize the portal circulation and cause intestinal schistosomiasis, and S. haematobtum, which colonizes the veins of the meter and bladder and causes urinary schistosomiasis. Figure 1 shows the geographic distribution of infection caused by the different schistosome species. S. mansoni is found in Africa, South America, the Caribbean (including Puerto Rico), and parts of the Middle East. S.japonicum is found only in eastern Asia and
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Figure 1• .Geographic distribution of schistosoine blood flukes is largely confined to. low latitudes. S. mansoni, a proi:ninent cause of .acute schistosomiasis and chronic intestinal schistosomiasis in humans, is endemic in parts of Africa, the Middle East, South America, and the Caribbean.
(It is the only New World schistosome.) S. haematobium; prominent in chronic urinary schistosomiasis, occupies parts of Africa and the Middle East. The Asian species S. japonicum and S. mekongi have disease manifestations similar to those of S. mansoni. Hospital Practice March· 15, 1991
119
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soni and S. japonicum for the intestine is responsible for characteristic differences in the manifestations of chronic schistosomiasis. Schistosome eggs excreted (4) into fres.h water develop into miracidia, or free-swimming first-stage larvae (5), which infect a snail intermediate host (6), in which they close their life cycle by developing and multiplying (7) into a new generation of cercariae.
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w. the Philippines. S. haematobium is found in Africa and portions of the Middle East. These geographic patterns are determined by the ecologic range of each schistosome's specific snail vector-the intermediate host in which the parasite undergoes much of its complex development. Because transmission from a snail vector to a definitive human host is limited to certain areas of the world, and indeed to certain regions within each endemic country, an important lesson of the cases described is that a detailed residence and
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travel history can be the first step in defining a patienfs risk. In rare cases, schistosomiasis is caused by the species S. mekongi (an S. japonicum-like species found only in Southeast Asia) and by S. intercalatum, an African parasite that produces both intestinal and urinary tract disease. Overall, schistosomiasis is the cause of clinical and subclinical morbidity (iron-deficiency anemia, malnutrition, and severe gastrointestinal or urinary tract involvement) in 7 4 nations around the world. Over the past decade, travelers from North America and Europe have been visiting schistosome-endemic areas With greater frequency. Such travelers, often poorly informed about the risk of acquiring schistosome infection, may have transient or prolonged contact With bodies of fresh water infested by cercariae, the stage of the parasite infective for human hosts, and thus may contract the infection unknowingly. Several features of the schistosome life cycle (Figure 2) have importantepidemiologic consequences. Schistosomes do not multiply Within the human host and cannot be passed directly from person to person. To be sure, the parasites mate in the human host. and the females lay their eggs in the human. However, the eggs must leave the hosfs body and hatch in fresh water if the life cycle is to continue. Moreover, in fresh water, the hatched parasite larvae must flnd their intermediate host: the snail in which they complete their multiplication and transformation into cercariae. This means that humans cannot acquire infection except through contact With freshwater sources populated With schistosome-infected snails. Thus, a detailed history of the type and duration of a patient's exposure to fresh water is a second useful step in considering the diagnosis of schistosomiasis. These etiologic and epidemiologic patterns are highly pertinent to both of the cases presented at the outset of this article.
Acute Schistosomiasis he first of the two cases described earlier represents a typical presentation of acute schistosomiasis, seen in a "Northern" traveler who visits or resides in a schistosomiasis-endemic area. For our patient, the first manifestation of exposure to the parasite was cercarial dermatitis, a papular or blistertngrash at the site of cercarial entry and primary skin migration. Such reaction is particularly common after exposure to S. mansoni or S. haetnatobium. The patient's subsequent syndrome of acute schistosomiasis, sometimes called snail fever or Katayama fever, is typically seen in adolescent or adult patients in the frrstinonths after primary exposure to S. mansoni or S.japonicum. Acute schistosomiasis manifests itself as a constellation of symptoms iiicluding fever, arthralgias, and abdominal pain. The symptoms are like those seen in an . allergic or serum sickness disorder. In fact, acute schistosomiasis
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appears to be mediated in!tially byimmediate and delayed-type hypersensitivity to cercarial and larval antigens, and later by involvement of immune complexes in a response to egg antigens. The more severe systemic manifestations of acute schistosomiasis develop after egg deposition begins. At that juncture, the hosfs exposure to parasite antigens becomes significantly greater, with consequent enhancement of the hosfirinnune response. A rare complication of acute schistosomiasis is attributable to aberrant migration of maturing worms into the central nervous· system. The migration may cause direct vascular occlusion by parasites or their eggs or occlusion of the.flow of blood or cerebrospinal fluid by granulomatous inflammation, which may lead, in either event, to seizures, hydrocephalus, acute or subacute paraparesis, or radiculopathy. Aberrant parasite migration to other organs may result in cutaneous egg deposition, leading to dermatitis, or egg deposition in the genital tract, leading to injury of the uterus. ovaries, vas deferens, or testes. Diagnosis of acute schistosome infection is often difficult, particularly in the early stages of infection, when migrating parasites may not have reached their final, favored location in the mesentery or the urinary tract and may not yet be passing eggs that can be detected by standard parasitologic examinations. In such cases, serologic studies are necessary to confum the patienfs exposure to schistosomes. (They were required in the case described.) Positive serology, however, does not exclude other causes of febrile illness. Exposure to water in locales where sanitation is poor carries a high risk of ingestion of toxins, viruses, or bacteria. Therapy for acute schistosomiasis is primarily symptomatic. In some cases, chronic infection does not become established, and symptoms resolve spontaneously before the diagnosis is discovered. In others, specific antiparasitic therapy may be required to eliminate ongoing disease or persistent infection. The patient described was treated because of persistent symptoms and in part as a therapeutic trial to establish a diagnosis. She would also have been treated if symptoms had resolved spontaneously but stool examination showed parasite eggs. A paradoxical response to an. tiparasite therapy is sometimes noted in patients with acute schistosomiasis. In such instances. a transient exacerbation of symptoms occurs because death of the parasite acutely increases the hosfs exposure to its antigens, accelerating the host immune response and worsening the immunopathology.
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Chronic Schistosomiasis
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within the human host, the intensity of infection increases only if the person has repeated contact with infested water. With continued exposure, the intensity of infection peaks at about age 13, after which the infection persists at low levels throughout most of adult life. For most patients, some manifestations, such as bleeding, ulceration, or polyposis, are a function of the concurrent intensity of infection. Such features are most common in teenagers and decrease in later life. Other manifestations are a function of cumulative exposure to the adult parasite and are more common in older patients. These include liver fibrosis and hydronephrosis. Host response to the parasite does vary, however. Some children may develop "late" complications due to very high levels of infection or a high degree of immune response to parasite eggs. The patient presented in Case 2 had many of the typical complications of chronic urinary schistosomiasis (due in his case to S. haematobium infection). But because his disease was slowly progressive and because his parasite burden was low at the time of diagnosis, the only clinical clues to suggest schistosomiasis were anemia, microscopic hematuria, and his history of travel. Because of the ease and efficacy of modern antischistosomal therapy, a screening parasitologic examination is probably worthwhile in any immigrant from a known endemic area. As in Case 2, curative therapy given early enough in the progression of injury can lead to regression of infection-associated abnormalities over a period of six months to two years after the therapy. The injury caused by schistosome infection in chronic schistosomiasis is initiated by the daily production of 300 to 3,000 eggs by each adult pair of worms. Because the eggs must pass from their point of deposition (in the venous circulation) to the lumen of the bladder or the bowel, only a fraction of the eggs succeed in leaving the body. At least 50% are trapped in host tissues. All in all, eggs represent the bulk of parasite antigenic material presented to the human host. Over a period of weeks, tissue-resident eggs are destroyed. The eggs become surrounded by host granulomatous inflammation mediated by delayed-type hypersensitivity. The mature granuloma contafus lymphocytes, macrophages, eosinophils, and neutrophils-each of which has a role in destroying the eggs. In contrast, worms resist both humoral and cell-mediated immunity. An important negative residual of the inflammatory process is the induction of fibroblast proliferation and collagen scar deposition. Clinically, the initial granulomatous inflammation is responsible for ulceration and polyp formation in the bowel (in intestinal schistosomiasis) or in the ureteral and bladder mucosa (in urinary schistosomiasis). The ulceration leads to bleeding, protein loss, and symptomatic mucosal irritation (diarrhea or dysuria), and sometimes to obstruction of th~ affected lumen. Over time, cumulative scar formation creates more advanced forms of infection-associated disease. In intestinal schistosomiasis,~~ese can include the clastracts of the liver. (The veins· sic "claypipestem" fibrosis in the portal •' are enlarged and are surrounde;d·by cuffs of white scar, making Hospital Practice March 15, 1991
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them look like pipestems in cross section.) The liver fibrosis caused by S. mansoni or S.japonicum is progressive, with an extent determined both by the total numger of eggs reaching the liver and by the exuberance of the host's grail.U:J.omatous response. Portal hypertension develops only after a sufficient level of infection is reached and enough time has passed for fibrosis to occur. Thus, fibrosis and portal hypertension are manifestations only of chronic schistosomiasis and are not seen in acute disease. Portosystemic shunting may occur without substantial injury to the metabolic function of the liver (and without abnormality in liver function studies), becau.se the loss in supply ofblood from the portal vein may be offset by a gradual arterialization of hepatic blood flow. However, the consequences of the portal hypertension in chronic schistosomiasis (as in cirrhosis) include both splenomegaly and variceal bleeding. Portosystemic shunting may also cause a large number of parasite eggs to reach the lungs, resulting in scattered pulmonary fibrosis and cor pulmonale.
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Figure 3. Transition from acute to chronic schistosomiasis appears to be accompanied by a downregulation of pathologic aspects of the host immune response. Mice were injected intraperitoneally with 25 S. japonicum cercariae and became host to an average of nine adult worms. Egg deposition, responsible for the bulk of the host exposure to parasite antigens, began during the acute phase of disease and continued throughout the chronic phase. Yetthe pathologic manifestations of intestinal sct)istosomiasis, including portal hypertension (top), peaked at about nine weeks and then declined. lmmunopathology concurrently peaked and declined, as measured by the mean cross-sectional area of granulomas around freshly deposited eggs (bottom). The experiment was conducted. by G. R. Olds and colleagues at . Cas~ Western Reserve University. Hoi;pital Practice March 15, 1991
In urinary schistoso:i;niasis, manifestations of chronic disease include hydronephrosis, hydroureter, bladder calcification, and a predisposition to ascending urinary tract infection by enteric bacteria. Long-term inflammation caused by S. haematobium eggs may result in neoplastic changes leading to the development of squamous carcinoma of the bladder. This tumor, seen at a rate of four per 100,000 population in regions where schistosomiasis is endemic, is exceedingly rare in developed countries, where transitional cell carcinoma is more common among bladder cancers. Although most young children who have urinary schistosomiasis experience hematuria, proteinuria, and anemia, some of the late sequelae of chronic infection, such as hydr.onephrosis and metaplasia, become manifest only after many years. Central nervous system involvement in chronic schistosomiasis does occur. It can be produced by any schistosome species but happens most frequently in chronic S.japonicum infection. As many as 4% of patients with this form of intestinal schistosomiasis may have seizures or show signs of hydrocephalus or space-occupying CNS lesions. In such cases, CT or magnetic resonance scans often show multiple areas of cranial involvement. The predilection of S.japonicum for the CNS remains unexplained. Chronic schistosome infection does not inevitably cause symptomatic disease. In village surveys within areas endemic for S. mansoni, hepatosplenomegaly is found in only 3% to 5% of infected persons. In similar surveys within areas endemic for S. haematobium, the prevalence ofhematuria is 30% to 50%, and ultrasound findings are abnormal in only 10% to 25% of infected persons. Overall, schistosomes produce clinical illness in only 5% to 20% of those who are chronically infected. This constitutes a success for the parasite, in that the host survives sufficiently well to provide nutrition to the long-lived invader (which has a life span of as much as five to 20 years)-nutrition that allows completion of (continues)
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the schistosome's complex life cycle. The exception to this "limited pathology" rule of host-parasite interaction in schistosome infection is found when persons from nonendeniic areas become lightly infected by transient exposure to high-risk water, as in Case 1. For these individuals, who did not "grow up" with the parasite, the inflammatory response to maturing parasites and their somatic and egg antigens is much more intense and causes significant immune-mediated systemic illness. The implication is that significant immunomodulation occurs in chronically infected individuals. Extensive study of the immune response in animal models of acute and chronic schistosomiasis suggests that infected animals do undergo a downregulation of the cellular immune response as disease passes from acute to chronic stages (Figure 3). The probable benefit to the parasite is increased survival of its eggs. The pr~bable benefit to the host, who cannot immunologically eliminate the mature worms, is reduction of im-
Figure 4. Diagnosis and Treatment of Schistosomiasis
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Hospital Practice March 15, 1991
127
mune-mediated injury. Evidence suggests that the maturation of the host response to parasite eggs may be associated with the development of a partial protective immunity to further parasite infection, but this association has not been definitively demonstrated in humans.
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n approach to the diagnosis and treatment of schistosomiasis .l"'l..is diagrammed in Figure 4. The nature of schistosome transmission dictates that the approach should be taken-in other words, the presumptive diagnosis of schistosomiasis should be entertained-only if the patient has lived or traveled in an endemic area. There persists in some textbooks and travel guides a misconception that schistosomiasis is acquired in endemic areas only from ponds or slow-moving rivers. These places are more dangerous than others, but experience has shown that even brief exposq.re to fast-moving water (as in a spill during white-water rafting) is potentially infectious. In sum, any exposure to unchlorinated fresh water in an endemic area may be significant. The manifestations of acute and chronic schistosomiasis caused by the different parasite species are summarized in Table 1. The features cited are typical-but they are hardly specific for schistosomiasis. Thus, the differential diagnosis of schistosome infection includes a long list of viral, bacterial, protozoa!, and helminthic diseases that are also highly prevalent in developing tropical areas. Statistics indicate that hepatitis, malaria, enteric fever, and intestinal helminths are more likely than schistosomiasis to affect the average traveler or immigrant. Nevertheless, if a patient has been at risk, schistosome infection should be considered and excluded, since continued infection may result in long-term morbidity. Diagnosis of chronic schistosomiasis is based primarily on the detection of parasite eggs in the patienfs feces or urine. It shoUld be noted that although species such as S. mansoni and S.japonicum .prefer the intestinal circulation whereas species such as S. haematobium prefer the urinary tract, crossover does occur, particularly in the area of the rectum and in heavy infection. Thus, S. mansoni eggs are sometimes found in the urine and S. haematobium eggs are sometimes found in the stool. Midday or 24-hour samples of urine and feces should be collected, and the parasite eggs in the samples should be concentrated (by any of several standard techniques) to increase the sensitivity for detection. Species identification is based on egg morphology (Figure 5) .and is necessary (as will be described) for selection of praziquantel dosages or for the choice of an alternative drug if praziquantel is contraindicated. In very light infection, egg release may be intermittent and a single day's testing may be falsely negative. Ifrepeated stool and urine examinations are negative and suspicion of infection remains high,
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endosocopy and tissue biopsy are indicated for recovery and identification of eggs. In most office practices, rectal biopsy is the procedure most readily available for diagriosis of intestinal and urinary schistosomiasis. For urinary schistosomiasis, cystoscopy may rarely be required to. obtain tissue for diagnosis. One caveat concerning biopsy is that patients who had chronic schistosomiasis many years earlier may still harbor dead but undestroyed parasite eggs. Active schistosome infection has been identified up to 20 years after the patient left an endemic area. Still, the usual life span of schistosomes is less than five years. The. longer the patient resides in developed areas, the less likely it is that any disease is related to schistosome eggs found on tissue biopsy. In endemic areas, a characteristic ultrasound finding of portal fibrosis (for intestinal schistosomiasis) or of bladder granulomas or polyps (for urinary schistosomiasis) in a patient with a history and physical examination strongly suggestive of chronic schistosomiasis may be sufficient eVidence to initiate therapy. As noted, diagnosis of acute schistosomiasis is sometimes difficult. It is an acute, febrile, flu-like illness typically seen in a patient whose background does not evoke the thought of parasites in the mind of the physician. Failure of patients to mention-or sometimes to recall-their travels certainly accounts for at least as much delay in the diagnosis of parasitic infection as the failure of physicians to think of such diagnoses. Moreover, patients with acute schistosomiasis may be most symptomatic in the prepatent period of infection, before worms become mature enough to produce eggs. For such patients, the diagnosis may be made only in retrospect, several weeks after infection, when symptoms have subsided but eggs are beginning to appear in the stool or urine. An alternative to searching for eggs as a diagnostic approach is to obtain serology for antischistosome antibodies. In the United States, the test is available at the Centers for Disease Control. The test is sensitive for past exposure to the parasite but does not determine the actiVity or intensity of current infection. Positive serology is most useful, therefore, in supporting the possibility of acute schistosomiasis. For adult patients from endemic areas, the test's specificity for active infection is too low for it to be used as a diagnostic tool.
Treatment ith the introduction of praziquantel in 1983, treatment of all forms of chronic schistosomiasis has become relatively straightforward. For patients infected by S, mansoni, S.japonicum, or the rare S. mekongi, an oral dose of60 mg/kg of body weight is given in two to three diVided ddses over a period of one day. For patients with chronic S. haematobium or S. intercalatum
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Figure 5. Morphology of schisto- · some eggs in feces or urine identifies the species and thereby determines the therapy. S. mansoni eggs (A) are blunt ovoid bodies about 140 µm long. S.japonicum eggs (B).are shorter and wider. Infection by either species is treated with 60 mg/kg of praziquantel given orally in two or three divided doses in.one day. S. haematobium eggs (C) are spindle shaped. Infection by this species is treated with 40 mg/kg of praziquantel as a single oral dose. Oxamniquine is an alternative for S. mansoni, niridazol e for S.japonicum, and metri'fonate for S. haematobium (although the last two drugs are not yet approved for use in the United States). Hospital Practice March 15, 1991
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disease, the treatment is 40 mgtkg as a single oral dose. Treatment is curative in 70% to 90% of patients, and the minority who fail to clear their infection usually show a reduction of more than 95% in egg excretion, indicative of a significant suppression of worm burden. "If egg excretion persists after a month, the therapy should be repeated at the same dosage. Side effects of praziquantel include sedation, malaise, headache, dizziness, abdominal discomfort, and nausea, but these symptoms are transient and occur in fewer than 15% of cases. Patients with extensive liver damage have higher blood levels of the drug, and side effects appear to be more frequent and more severe. Concern has been expressed about the use ofpraziquantel in areas endemic for cysticercosis (tissue infection with Taenia solium tapeworm larvae). Approximately 20% of patients with neurocysticercosis experience heightened neurologic symptoms when the tapeworm infection is treated with long-term praziquantel therapy. To date, however, such reactions have not been noted in largescale schistosomiasis treatment programs-in which only singleday therapy is used. Moreover, praiiquantel has been shown to yield specific benefit in CNS schistosomiasis associated with S. japonicum infection. Symptoms improved and radiographic lesions regressed over several months.
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Selected Reading Ash LR, Orihel TC: Parasites: A Guide to Laboratory Procedures and Identification. ASCP Press, Chicago, 1987,pp55-57,80 Case Records of the Massachusetts General Hospital: Case 21-1985.NEnglJMed312:1376, 1985 Centers for Disease Control: Acute schistosomiasis in U.S. travelers returning from Africa. MMWR39: 141, 1990 King CH, Mahmoud AAF: Drugs five years later: Praziquantel. Ann Intern Med 110:290, 1989 Mahmoud AAF, Abdel Wahab MF: Schistosomiasis. In Tropical and Geographical Medicine, 2nd ed, Warren KS, Mahmoud AAF (Eds). McGraw-Hill, New York, 1990 Warren KS, Mahmoud AAF (Eds): Geographic Medicine for the Practitioner, 2nd ed. Springer-Verlag, New York, 1985, pp 176-182
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The drug oxamniquine is available as alternative oral therapy for S. mansoni. Metrifonate (not approved by the U.S. Food and Drug Administration) is an oral alternative for treatment of S. haematobium, and niridazole (also not FDA approved) is an oral alternative for S. japontcum. These "investigational" drugs have actually been used extensively as antischistosomal therapy outside the United States, but for patients from some areas, they may be less effective than praziquantel in achieving a parasitologic cure. It appears that resistance to the alternative drugs is more common in areas where they have been used extensively in the past. Therapy for acute schistosomiasis has been studied less well than has the treatment of chronic disease. Since it appears that the acute syndrome is a manifestation of host response to limited parasitic infection, specific antiparasitic therapy may not influence the course of the illness. Nevertheless, it is important to eliminate the infection when it has been diagnosed, and most patients tolerate standard therapy with praziquantel quite well. Some patients do experience an exacerbation of symptoms after treatment and may require a short course (days) of anti-inflammatory drugs. Schistosome infection is responsible for a variety of acute and chronic illnesses. Diagnosis and therapy are relatively straightforward. The problem is that suspicion of the infection must be evoked-by a patient's history of travel or residence in endemic. areas, with possible exposure to the parasite-before it can be part of a differential diagnosis. Increased experience by North American physicians will lead to a better understanding of the underlying pathology, and secondarily to a better understanding of the ins and outs of diagnosis and treatment. · o
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