Human Infections with Sarcocystis Species

Intestinal Sarcocystosis Species and SymptomsHumans with intestinal sarcocystosis (Fig. 1) have been identified worldwide, with the exception of Africa and the Middle East, although such infections likely occur there given customs of eating raw or undercooked meat in those areas. Locations where cases of intestinal sarcocystosis have been reported are listed in Table 3, including infections that resulted after volunteers ingested naturally infected or experimentally infected meat (6, 7, 35 – 68). Early investigators, with no knowledge of the Sarcocystis life cycle, observed two parasites with characteristics of apicomplexan oocysts in stool samples of infected persons and named one Isospora belli, which was excreted as a distinctive unsporulated (internally undifferentiated) oocyst, unique in size and shape and unlike any other apicomplexan parasite. The other coccidian parasite, excreted as a sporulated oocyst (containing sporocysts with sporozoites) or as individual sporocysts, was named Isospora hominis (35, 37, 39, 44) and represented what is now recognized as multiple species of Sarcocystis, two of which are known to be S. hominis (6, 40, 41, 46 – 48, 51, 53, 54, 58, 59) and S. suihominis (6, 40, 50, 53, 62). However, other species may have been present because the oocysts and sporocysts of Sarcocystis species are morphologically indistinguishable. Most reports cite infections in persons in European countries, including The Netherlands, Germany, Poland, Slovakia, France, and Spain (Table 3). In Asia, infections have been reported in China, Tibet, Laos, and Thailand (Table 3). Other cases have been reported in Australia, Argentina, and Brazil (Table 3).

As definitive hosts, humans can experience nausea, vomiting, acute and severe enteritis, or chronic enteritis, but many infections appear to be mild or asymptomatic. Differences depend on the number, and perhaps the species, of sarcocysts ingested. Few accurate data are available on the duration of infection or the numbers of oocysts and sporocysts excreted. Most case studies suffer from not knowing the time of onset of infection, the type or quantity of meat consumed, the species and number of sarcocysts consumed, and whether a patient ingested raw meat once or multiple times. The longest period of continuous sporocyst excretion (I. hominis) was 21 months or more for a patient in The Netherlands, while other patients excreted sporocysts for at least 6 months (35). A patient in Poland excreted sporocysts for at least 12 months (36). However, the most reliable information on the prepatent and patent periods is from human volunteer studies. In Germany, diaphragms from cattle and pigs were obtained from an abattoir, ground in a meat grinder, and found to contain zoites of Sarcocystis. This ground meat was then fed to volunteers who were not excreting oocysts or sporocysts in their stools (6). In the first experiment, two volunteers ate 500 g of raw beef diaphragm with onions and spices and began excreting sporocysts 9 days later, continuing for 40 days or longer. In the second experiment, four volunteers ate seasoned raw pork diaphragm and began excreting sporocysts 9, 13, and 17 days later; the fourth person remained uninfected. The patent period for the three volunteers was at least 30 days. For a volunteer in China who ingested S. suihominis-infected pork, the prepatent period was12 days, and the patent period was >120 days (50). Another volunteer excreted sporocysts from days 8 to 40 after eating beef (51). Two other volunteers in China who ate beef and three who ate water buffalo had prepatent periods of 10 to 12 days and patent periods of 11 to 29 days (57). Another volunteer in China excreted sporocysts of S. suihominis for an estimated 91 days beginning 10 days after eating pork (62). Of seven volunteers in Brazil who ate raw kibbe (beef), six began to excrete S. hominis oocysts/sporocysts 10 to 14 days later and excreted them for 5 to 12 days (58).

Intestinal Sarcocystosis in EuropeIn The Netherlands, oocysts and sporocysts were identified as I. hominis in stool samples of 17 of 72 persons, some without illness and others suspected of suffering from chronic amoebiasis; additionally, in 5 of 17 subjects, intestinal mucosa scrapings taken at autopsy contained sporocysts of I. hominis (35). Also, in The Netherlands and in various other countries between 1960 and 1970, several surveys were conducted, in which stool samples from humans were examined (69). Ten percent to >50% of persons excreting sporocysts were in countries where raw meat was usually consumed. In a subsequent survey in The Netherlands, babies born to mothers who excreted sporocysts began excreting sporocysts at 9 to 10 months of age, correlating with them being fed raw or partially cooked, minced beef (69). In Poland, a 29-year-old woman working in an orphanage had single and double sporocysts in her feces for 12 months (36), which could have resulted from repeated reinfection. Neither her family nor her coworkers were found to be positive, but later, 7 persons at the orphanage were found to be infected, and at other locations in Szczecin Province, 92 additional persons were found to be infected.

In Germany, of 150 stool samples examined, I. hominis was detected in 12 persons who had eaten raw beef or pork (38). Six of the 12 persons had different gastric or intestinal symptoms, and 6 were asymptomatic. Also in Germany, a volunteer consumed 100 to 200 g of raw beef naturally infected with S. hominis or meat from cattle experimentally infected with S. hominis for 1 to 3 days on four separate occasions at intervals of several months (40). The volunteer had low-grade clinical symptoms of stomachache, nausea, and diarrhea beginning 3 to 6 h after meat consumption; symptoms lasted 24 to 36 h. Diarrhea and stomachache were again present when most sporocysts were excreted 14 to 18 days after the meat was consumed. Again in Germany, three volunteers who consumed 100 to 400 g of raw minced pork from pigs heavily infected with S. suihominis became symptomatic beginning 6 to 8 h later, with diarrhea, dyspnea, vomiting, bloat, nausea, stomachache, inappetence, and rapid pulse (40). Symptoms continued up to 48 h. Well-cooked pork from the same pigs caused no clinical symptoms in nine other volunteers who ate the meat. Based on these observations, S. suihominis was considered either pathogenic or toxic for humans. Others concluded that such pathological effects were due to toxicity (69).

In eastern Slovakia, a 12-year-old girl hospitalized for tuberculosis was incidentally found to be excreting oocysts and sporocysts of I. hominis in her stool (44). In central Slovakia, of 1,228 Vietnamese workers who immigrated over a period of 18 months, 14 excreted sporocysts of Sarcocystis for a mean of 49 days, with no gastrointestinal symptoms (52).

Intestinal Sarcocystosis in AsiaIn Thailand, six patients 3 to 70 years of age with acute enteritis and leukocytosis underwent resection surgery of the ileum (48). The histopathological diagnosis indicated segmental eosinophilic enteritis or segmental necrotizing enteritis. Sexual stages and developing oocysts resembling those of Sarcocystis were observed in resected tissues from one patient, and sporocysts and numerous Gram-positive bacilli were observed in tissue samples from five others. Because sarcocysts were present in local market beef from Bos indicus cattle, and the patients ate raw beef in chili dishes, the authors of that report concluded that the cattle-human parasite S. hominis was responsible for the infections. In northern Thailand, Sarcocystis was found in 23.2% of stool samples from 362 asymptomatic laborers, 83.3% of whom were males (55). Of 253 stool samples from 140 female and 102 male villagers 2 to 80 years of age in Kaen Province, northeastern Thailand, 0.4% were positive for S. hominis (66). Of 479 stool samples collected from rural Ubon Ratchathani Province and 1,124 stool specimens from Khon Kaen in Thailand, 4.6% and 8% were positive for Sarcocystis (63). These findings and others (55, 66) suggest that northern Thailand is an area where enteric sarcocystosis is endemic. In neighboring Laos, stool samples from 1,008 persons were examined, and S. hominis was present in >10% of samples from persons >20 years of age (54).

In Tibet, stool specimens from 926 persons from Linzhi, Milin, and Duilongdeqing counties were examined by the zinc sulfate flotation method, and S. hominis was detected in 20.5 to 22.9% of the specimens in the three counties (53). S. suihominis was detected in 7.0, 0.6, and 0% of the specimens, respectively (53). Cases were usually asymptomatic, and most became negative after an undisclosed treatment.

In China, of stool specimens examined from 12 persons, single and double sporocysts were found in specimens from two men (49). No information was provided for one man, but the other, 48 years of age, had abdominal distention and pain, with alternating diarrhea and constipation and with stomachache and dyspnea. He had eaten raw pork between 13 and 65 days before his examination, and because he also had ova of Ascaris in his feces, the sporocysts were assumed to be those of S. suihominis. However, the presence of Ascaris cannot be accepted as a valid reason for assuming that sporocysts were S. suihominis without additional information. In Yunnan Province, China, a volunteer developed dizziness, abdominal pain, anemia, and diarrhea 3 days after consuming 60 g of raw beef from a calf experimentally infected with S. hominis (51). Also in China, three volunteers consumed >1,500 sarcocysts in skeletal muscles from naturally infected cattle, and two other volunteers ingested >14,000 sarcocysts in water buffalo meat (57). Beginning a week after ingestion and ending spontaneously 3 weeks later, symptoms included abdominal pain and swelling, diarrhea, and eosinophilia. In Guangxi, China, a volunteer who ate fresh pork containing sarcocysts of S. suihominis had abdominal distension beginning 5 h later, and from 8 to 36 h, he had watery diarrhea followed by fever; chills; dizziness; headache; muscle, joint, and upper abdominal pain; as well as loss of appetite (62). Another volunteer in China who ingested raw beef developed abdominal distention on the day that he consumed it; on the following day, he had stomach pain and diarrhea that lasted for 28 days (65). Sarcocystis hominis sporocysts were found in stool samples 11 to 29 days after consumption of beef (65). In two countryside villages in Guangxi, 22 men and 5 women out of 501 persons examined were excreting oocysts identified as Sarcocystis suihominis based on the finding that all persons had a history of eating raw pork (60). Of 247 men and 254 women in that study, 26 persons with positive specimens were >30 years of age, 8 had diarrhea and abdominal pain, 1 had only abdominal pain, and the others had no symptoms. It is not clear if those authors revisited one of the same villages, but similar results were reported, in which 32 of 489 fecal specimens from the Zhuang ethnic population were found to be positive for S. suihominis (61).

In India, the prevalence of S. suihominis in pigs and humans was high in an economically deprived sect (70, 71), probably linked to slaughter practices. A selected group of 20 children between 3 and 12 years of age belonged to families who reared pigs and slaughtered them in their backyard for selling pork for human consumption (71). The children of these families consumed the offal, including parts of the tail, which they ate raw with salt. The stools of these children were examined daily for 2 weeks, and 14 children, all of whom complained of abdominal pain and diarrhea, excreted sporocysts of Sarcocystis (71).

Intestinal Sarcocystosis in AustraliaAt a local hospital servicing five aboriginal communities in Western Australia, a 4-year parasitological survey was conducted, in which fecal specimens from 385 children and adults were examined (56). Sarcocystis detected in 2 specimens was attributed to adverse living conditions and inadequate hygiene.

Intestinal Sarcocystosis in North and South AmericaIn each of two studies, a human volunteer and two dogs ate beef products from a retail grocery store in Maryland, and feces were examined daily for ∼3 weeks thereafter (45). In the first study, 227 g of undercooked roast beef was eaten daily for 5 days, and in the second study, 227 g of raw ground beef was eaten daily for 3 days. Because both dogs in both studies became infected, whereas the human volunteer did not, the findings suggested that S. cruzi was present and infectious in both types of beef. Neither the dogs nor the volunteer exhibited any clinical symptoms of infection.

Sarcocystosis was detected in stool and in duodenal and liver biopsy specimens from a 31-year-old AIDS patient in Argentina who had chronic diarrhea, hepatitis, and muscle pain (64). Sexual stages were seen in the lamina propria, sporulated oocysts were found in the stools, and schizont-stage parasites were seen in the liver. However, the illustrated objects do not appear to be schizonts, and other findings are inconsistent with what is known of the life cycle. Because those authors provide no explanation for these differences, the conclusion that these stages represent Sarcocystis is considered doubtful. A second, unrelated infection with another protist might explain this inconsistency. In 25 Arabian restaurants in Brazil, Sarcocystis was found in 50 samplings of kibbe (58). During a second period of collection, of four men and three women volunteers who ate between 128 and 260 g of kibbe, six excreted S. hominis oocysts/sporocysts in stools. Two volunteers had clinical symptoms: one had abdominal pain 1 day later and diarrhea for the first 3 days after eating the kibbe, and the other had diarrhea 11 days after eating the kibbe.

Diagnosis of Intestinal SarcocystosisThe basis for a presumptive diagnosis of intestinal sarcocystosis includes enteritis and a history of having consumed undercooked meat, although infected persons can be asymptomatic. Confirmation requires identification of oocysts and or sporocysts in the stool. Sporocysts with sizes of ∼10 by 15 μm are easily seen by LM in a wet preparation just below the coverslip in a droplet of aspirated fluid from the surface of a fecal float and will autofluoresce when viewed by fluorescence microscopy. Flotation is performed by mixing feces with concentrated solutions of zinc sulfate, sucrose, sodium or cesium chloride, Percoll, or similar high-density solutions, followed by centrifugation at 500 × g to sediment fecal debris while concentrating the parasites at the surface (1). Species cannot be distinguished from one another by this method because they are so similar morphologically. The presence of asexual stages and sporulated oocysts in the intestine is more applicable for postmortem diagnosis, but biopsy or postsurgical specimens can reveal the presence of infection when stool specimens appear negative.

Extraintestinal SarcocystosisHumans can become infected with unknown numbers of Sarcocystis species acquired by ingesting contaminated food or water containing sporocysts excreted by infected carnivores (Fig. 2). In such cases, humans serve as an accidental and aberrant intermediate host, replacing the intermediate host found in nature. Based on studies of animal intermediate hosts, multiple generations of asexual reproduction develop in the vascular endothelium and in circulating monocytes, followed by the development of sarcocysts in myocytes of skeletal, cardiac, and smooth muscle. Based on animal studies, sarcocysts are the end stage in intermediate hosts. Sarcocysts may rupture from time to time, but the released bradyzoites die and are not known to initiate new infection.

Until recently, <100 humans had been diagnosed with muscular sarcocystosis (32). Most cases were diagnosed by use of incidental biopsy specimens, with no associated clinical symptoms, or at autopsies in tropical countries, of which nearly 50% worldwide were in Malaysia (8, 16, 17, 22, 24, 72). Of the 40 infections reviewed by Beaver et al. (8), 13, 8, 5, 4, 4, 3, and 1 were probably acquired in Southeast Asia, India, Central or South America, Africa, Europe, the United States, and China, respectively. Reports from Africa, the Middle East, and Central and South America continue to be rare or lacking. Examination of tongue muscle obtained at autopsy was extrapolated to suggest a sarcocystosis prevalence rate of ≤21% among Malaysians (17), although none of the >1,500 muscle biopsy specimens from limbs of patients with various muscle diseases, acquired over a 20-year period at the Medical Centre of the University of Malaya, are reported to have yielded sarcocyst-positive tissues (25). Until the 21st century, only ∼10 cases were reported to be symptomatic with acute muscular sarcocystosis (18, 19, 21, 73). All infections in humans until 2013 were reported as intramuscular sarcocysts of unknown species. Since then, studies of two separate outbreaks in Malaysia have identified S. nesbitti as the causative species and one capable of infecting humans (25 – 28).

Diagnosis during the early period leading to muscular infection is difficult because symptoms are nonspecific. Based on observations from outbreaks and experimental animal studies, muscular sarcocystosis might be suspected when a patient presents with a history of travel or residence in a tropical country, especially in Southeast Asia, and with various combinations of fever, myalgia, headache, cough, episodic weakness or fatigue, and arthralgia (21, 27, 28). This early phase of disease also might not present with objective laboratory abnormalities. Nonspecific and slightly elevated levels of hepatic enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), inflammatory markers (C-reactive protein and erythrocyte sedimentation rate [ESR]), or markers of general cell damage (lactic dehydrogenase [LDH]) might be encountered. Later, with the onset of myositis, muscle tenderness upon physical examination and possibly elevated serum creatinine phosphokinase (CK) levels and blood eosinophilia might be found. With negative test results for Toxoplasma and Trichinella, a presumptive diagnosis of sarcocystosis should be entertained. The detection of sarcocysts in a muscle biopsy specimen would confirm the diagnosis, although parasites might be diffusely distributed and difficult to find. Magnetic resonance imaging (MRI) has been suggested to be of benefit in guiding the choice of muscle biopsy site (27), although there is no evidence showing this method to be superior to guidance using physical examination findings, such as palpation to locate a point of maximal tenderness, visual observation to identify regions with swelling, or touch to identify areas of increased warmth. LM examination of stained histological sections and those with a positive periodic acid-Schiff reaction of the sarcocyst wall facilitate identification. Although eosinophilic myositis, muscle inflammation and necrosis, and interstitial and perivascular inflammation can be seen in some cases, inflammatory cells are not often observed in close proximity to sarcocysts (21, 27, 28, 74).

An accurate and sensitive diagnostic test is needed to improve diagnosis. Enzyme-linked immunosorbent assays (ELISAs), immunofluorescence assays (IFAs), and other serologic tests for antibody to Sarcocystis using bradyzoite antigen have been limited to specialized laboratories, have not been standardized, are not widely available, and have other inherent problems (75). Most of these tests no longer exist because there has been little or no continued demand for their use. In addition, the specificity of serologic assays for muscular versus intestinal sarcocystosis has not been proven, and cross-reactivity with other apicomplexans could be problematic. Development of a molecular method to detect Sarcocystis DNA in human blood or muscles could facilitate early diagnosis by expeditiously confirming the cause of the infection and identifying the species involved, all in one test. PCR has been applied for diagnostic blood testing in animals and might have the capability of detecting low numbers of circulating parasites at an early stage of infection, during merogony, at a point before entry of the organism into muscles (76).

Outbreaks and Case DescriptionsMuch can be learned of the clinical signs of intramuscular sarcocystosis, the potential routes of infection, and the sources of infection from outbreaks. A series of outbreaks in Malaysia have been recorded (21, 25 – 30).

During a civic project in 1993 in Malaysia, seven members of a U.S. Air Force team were deployed for 1 week ∼80 km northeast of Kuala Lumpur in or near a jungle village (21). The seven persons had extensive opportunity for potential exposure to sporocysts in the environment from working shirtless and shoeless during heavy monsoon rains, by exposing themselves to possibly contaminated swimming and drinking water and soil, and by eating fresh vegetables that might not have been well cooked. Within 3 weeks after returning from deployment, two members of the jungle cohort presented with acute fever, myositis, and bronchospasm, with elevated liver enzyme levels and eosinophilia. Seven members of the jungle cohort, one of whom was asymptomatic, were tested for eosinophilia, sedimentation rate, and serum enzyme levels, including ALT, CK, LDH, and AST levels, and virtually all subjects had at least some levels elevated above normal. The timing of these laboratory determinations with respect to symptom onset or time beyond departure from the jungle area was not reported. Four subjects developed bronchospasm, myalgia, skin lesions, and swollen lymph nodes within 2 months after leaving Malaysia, which waxed and waned over the following 6 months, but two were much more symptomatic, with intermittent fevers, myalgias, arthralgia, muscle wasting, weight loss of 6 to 9 kg, fatigue, headache, and rashes. One of these two subjects remained symptomatic for several years, with a waxing-waning course; this patient underwent a muscle biopsy 3 months after illness onset, and sarcocysts were observed histologically. About a year later, possible Sarcocystis-related myocarditis was diagnosed based on borderline left atrial enlargement with electrocardiogram (ECG) abnormalities. These cardiac abnormalities subsided over the following year, but 5 years from the onset of illness, he still reported occasional episodes of pruritus, abdominal tenderness, and subcutaneous nodularity.

Another outbreak of muscular sarcocystosis included college students and teachers who visited Pangkor Island in the Malacca Strait of Malaysia (25 – 27). Of 92 persons who attended a retreat on the island, 89 became symptomatic within 26 days after leaving the island. Symptoms included fever (94%; 57% relapsing), myalgia (91%), headache (87%), and cough (40%). Eight persons with facial swelling for 4 to 6 weeks showed changes in their muscles of mastication by whole-body MRI consistent with inflammatory edema (27). Similar findings were observed for the back muscles of four persons and the calf muscles of two others. Four symptomatic patients underwent muscle biopsy. Of these patients, at least one sarcocyst was observed in the biopsy sections of three patients; a fourth specimen was definitively determined to be positive by PCR. Of the four patients with confirmed muscular sarcocystosis, two had elevated serum CK levels, and three had eosinophilia; however, the timing of these laboratory investigations was not well described (27). Sequences of 18S rRNA extracted from ground temporalis muscle tissue excised from one patient and from leg muscle of another matched 100% with sequences reported for Sarcocystis nesbitti (34), suggesting that sporocysts in snake feces were the probable source of infection. Although snake feces were collected from several sites in Malaysia, including Pangkor Island, Sarcocystis sporocysts were not recovered, but PCR evidence of S. nesbitti was found in feces of a cobra (Naja naja) collected in peninsular Malaysia (26).

Two waves of infection in 2011 and 2012 involved 99 tourists who vacationed on Tioman Island in the South China Sea off the Malaysian coast; all subjects were Europeans, except for two residents of Canada and a British resident of Singapore (28). Sixty-eight patients met the case definition, with myositis, eosinophilia, and negative trichinellosis serology. Diagnosis of myositis required at least one of the following signs: a complaint of muscle pain with a serum CK level of >200 IU per liter, muscle tenderness documented upon physical examination, or histological evidence of myositis in a muscle confirmed by biopsy. Sixty-two patients were considered probable cases, and six cases were confirmed by histological observation of intramuscular cysts compatible with sarcocysts. Symptoms that clustered during the second week and the sixth week after returning from the island included fever (82%), myalgia (100%), and headache (59%), similar to the symptoms of visitors to Pangkor Island, as well as fatigue (91%) and arthralgia (29%). Blood eosinophilia and elevated serum CK levels were first observed during the fifth week postdeparture. DNA recovered from sarcocysts in one biopsy sample identified the infecting species as Sarcocystis nesbitti. These first two waves of infection in 2011 and 2012 were associated with travel during the summer. No patients meeting the case definition were reported in 2013, but a series of infections in travelers returning to Germany from the same island was diagnosed beginning in the early spring of 2014 (30).

Additional data collected from 39 German patients with a history of travel to Tioman Island during 2011 to 2014, some of whom were included in the first report (28), were examined longitudinally (31). These patients had periods of illness from ranging from 0 to 23 months (median duration, 2.2 months), with 17% having symptoms lasting >6 months. Two patients had unresolved but diminished symptoms at 13 and 23 months. The median severity of pain on a scale of 0 to 10 was 6 (range, 0 to 10). This was the first study of the duration of muscular sarcocystosis in multiple patients.

Sarcocystosis and CardiomyopathyIn 11 of the 40 cases cited by Beaver et al. (8), sarcocysts were found in heart muscle at autopsy. Sarcocysts appeared to be of three morphological types, suggesting three possible species. Seven persons were from the Caribbean and Central and South America. In one case, an 8-year-old boy in a hospital in Costa Rica was diagnosed with cardiac insufficiency and died 13 days later (8). One year earlier, he had been diagnosed with rheumatic fever. The autopsy revealed bilateral pulmonary thrombosis with infarction and chronic cardiopathology. Histopathology revealed numerous sarcocysts in cardiac muscle, with no associated inflammatory reaction. The morphology of the sarcocysts resembled that of sarcocysts found in myocardium in two other autopsy cases, one of whom had sarcocysts in Purkinje fibers.

Of the 68 confirmed cases associated with the outbreak on Tioman Island, Malaysia, 10 patients had a mildly elevated CK MB fraction (i.e., the bound combination of isoenzymes creatinine phosphokinase M and creatinine phosphokinase B), and 8 patients had a normal electrocardiogram, echocardiogram, or troponin level, but none were considered to have cardiac pathology (28). One patient had an echocardiogram showing mild dilatation of right ventricular outflow and was thought to have mild myocarditis, which ultimately resolved.

Sarcocystosis and GlomerulonephritisAlthough glomerulonephritis associated with acute sarcocystosis with schizonts in the glomeruli is characteristic of S. cruzi infection in cattle, there is only one human case, in which a 47-year-old Indian man with intramuscular sarcocysts and glomerulonephritis was described (24). Whether the two were related or coincidental could not be established.

Sarcocystosis and MalignancySeveral cases of sarcocystosis have been detected in patients with various types of cancer.

At this time, insufficient data are available to clearly link sarcocystosis as an underlying cause or consequence of malignancy.

In Malaysia, when a patient with a malignant brain melanoma was examined to find the primary tumor site, sarcocysts were discovered in the nasopharynx and oropharynx (77). Subsequently, in Malaysia, 8 of 11 muscular sarcocystosis cases were persons with malignancies, mostly those of the nasopharynx and tongue (16). In Malaysia and other parts of Southeast Asia, many residents chew betel leaves in combination with other ingredients such as tobacco. In Sri Lanka, for example, a high prevalence of potential oral malignancies was associated with betel-quid chewing (78), so factors other than sarcocystosis that might contribute to malignancy cannot be ignored. Another case of malignancy with intramuscular sarcocysts that was reported in Malaysia involved a 44-year-old woman with progressive swelling, pain, and weakness of the midthigh; this was diagnosed as a malignant histiocytoma with sarcocysts in muscle fibers deep within the lesion (20). Of 1,063 laryngeal biopsy specimens examined in Thailand, only a single case of sarcocystosis concomitant with squamous cell carcinoma of the larynx was found (23). These contrasting findings provoke several hypotheses: (i) immunosuppression associated with malignancy might facilitate opportunistic parasitism with Sarcocystis, (ii) sarcocystosis might cause malignancy, or (iii) sarcocystosis in cancer patients might be coincidental in locations where there is a high prevalence of sarcocystosis. Ultimately, Shekhar et al. (20) concluded that there was no evidence of tissue reaction at the site of the parasite to induce neoplastic changes. Those authors did not consider the possible effect of earlier developmental stages or of other environmental or cultural factors. For example, areca nut, sometimes mixed with tobacco, slaked lime, and various spices, is chewed by millions of Indo-Asians and is strongly associated with cancer risk (79).

Intestinal SarcocystosisAlthough intestinal infections do not involve multiplication, development in the intestine consists of either a male or female stage from each bradyzoite within a sarcocyst. Therefore, such infections are self-limiting. Although some infections appear to persist for long periods, others might actually be the result of reinfection and the lack of protective immunity. A report of a volunteer who repeatedly infected himself by consuming sarcocysts in pork and beef suggests that there is little or no protective immunity to repeated intestinal infection (40). Neither prophylaxis nor therapeutic treatment for intestinal sarcocystosis of either animals or humans has been developed.

A patient with enteritis was diagnosed with Strongyloides stercoralis and I. hominis (Sarcocystis) infection and was treated with dithiazanine, but Sarcocystis persisted (35). Pyrimethamine, prescribed at 37 mg daily for 5 days and then at 25 mg daily for 10 days in combination with sulfisoxazole at 3 g per day for 14 days, was also not successful (44). A volunteer who ingested S. suihominis sarcocysts was treated with acetylspiramycin for 15 days at a dose of 0.2 g four times a day, but excretion did not stop until 30 days later (62).

Muscular SarcocystosisThere are no vaccines to provide protection against muscular sarcocystosis, but protective immunity following an initial infection has been demonstrated in animals. Prophylaxis for muscular sarcocystosis was successful when the anticoccidial drugs amprolium, salinomycin, and halofuginone, designed to prevent Eimeria infections in poultry and livestock, were administered at the time of experimental infection in animal studies (80 – 83). Activity against the early development of asexual stages has been found, but efficacy for therapeutic treatment once intramuscular cyst formation has begun has not been investigated under experimentally controlled conditions. When salinomycin was administered to lambs for 29 days beginning 1 day before 100,000 or 1 million S. tenella sporocysts were fed, clinical sarcocystosis was reduced, but completion of the life cycle by some of the parasites was not prevented. At 63 days after the initial infection, lambs given salinomycin were challenged with 1 million S. tenella sporocysts and were found to have developed protective immunity (82). This might explain, at least in part, why foreign tourists to Tioman Island and not the local indigenous population became ill, if it is assumed that the local indigenous population was infected some time earlier (28, 84), and why native Malaysian students did not appear to become as ill as the foreign students during the Pangkor Island outbreak (27).

Severe Sarcocystis myositis in two dogs with fever, lymphopenia, thrombocytopenia, and elevated ALT and CK levels was confirmed by muscle biopsy (85). Treatment with anti-inflammatory drugs and clindamycin was unsuccessful. One dog recovered after treatment with decoquinate (an anticoccidial drug). The other dog died. Consequently, it is not clear if any antiparasitic drugs used for treatment after sarcocysts form are effective or if waning symptoms are the natural course of the infection.

Treatment of a patient involved in the outbreak among U.S. Air Force personnel in rural peninsular Malaysia began with 400 mg albendazole twice daily for 15 days, 18 months after symptoms began (21). Treatment elicited intense pruritus, but chronic symptoms gradually waned, and therapy was then discontinued. After several weeks, discomfort returned; therapy was initiated at 600 mg twice daily for 20 days, and symptoms abated. Those authors note that it was unclear if improvement was related to the use of albendazole or reflected the natural history of the infection. Patients returning from Tioman Island, Malaysia, received treatment with various antiparasitic agents, including albendazole, and some received treatment with oral steroids (28). Some clinicians reported relatively rapid symptom improvement resulting from oral steroids, including a patient with mild myocarditis who responded favorably to such treatment.

The antiprotozoal drug co-trimoxazole (trimethoprim at 160 mg and sulfamethoxazole at 800 mg), given as a dose of 3 tablets per day for 12 days, was used to treat a 31-year-old male patient >3 months after muscular pain began (18). He was already feeling slightly better when diagnosis was made and before medication was prescribed but greatly improved, except for some localized pain.

Of three patients who sought medical attention within 6 days of onset of fever and were treated with co-trimoxazole (a 960-mg dose twice each day), all improved clinically without an elevation of CK levels (30). Two other patients in a later phase of illness with elevated CK levels were also treated with co-trimoxazole, but one had to be re-treated with prednisone because of increasingly severe myalgia. A sixth patient, who had the longest interval from the onset of symptoms, was treated with prednisone. Both patients treated with prednisone improved rapidly.

Sulfathiazole, sulfamethazine, sulfamethoxazole, sulfadimethoxine, sulfadiazine, sulfachloropyridazine, trimethoprim, and pyrimethamine were tested at different concentrations in cell cultures against developing S. neurona merozoites (86). Pyrimethamine and trimethoprim were each cidal, but none of the sulfonamides had activity when used alone. Combinations of sulfonamides demonstrated improved activity.

What is lacking is a protocol that has been tested, found to be effective, and confirmed by replication. Because it is impractical and undesirable to use humans or primates for testing, it would be helpful as new patients are identified to report successful and unsuccessful treatment regimens. However, because symptoms usually wane with time, the efficacy of long-term medication might not be discerned from the natural course of the disease process.