Sarcocystosis

INTRODUCTION — Sarcocystosis is a zoonotic infection caused by a protozoan parasite of the genus Sarcocystis, of which there are more than 200 known species [1-4]. Depending on the infecting species and nature of the ingested material, two distinct clinical syndromes may occur in humans: intestinal sarcocystosis or muscular sarcocystosis.

Three species of Sarcocystis have been identified in human infection [5,6]. Sarcocystis hominis and Sarcocystis suihominis cause gastrointestinal disease; humans serve in the natural infection cycle [5]. Sarcocystis nesbitti, a snake species, has been recognized as a cause of human muscular sarcocystosis in Malaysia; humans are accidental, dead-end intermediate hosts [6].

EPIDEMIOLOGY — Livestock universally harbor Sarcocystis infection worldwide. Symptomatic and asymptomatic gastrointestinal infection has been reported with the highest prevalence in Europe; cases have also been reported from many Asian countries, with less frequent occurrences in Australia and North and South America [5,7-11].

Of the almost 200 cases of symptomatic human muscular sarcocystosis reported in the literature, the majority have occurred as part of outbreaks or case series originating from rural Malaysia [7,10-17]. The best description of the natural history of sarcocystosis is reflected in a report of 89 cases that occurred during a definitive point-source outbreak in early 2012 on Pangkor Island off the west coast of Malaysia [14]. Subsequently, 68 cases presenting late in the clinical evolution of disease were attributed retrospectively to exposures on Tioman Island off the east coast of Malaysia in 2011 and 2012 [15]. Other countries with reported exposure include India and Thailand [18-21]; two symptomatic cases have been described with no evident exposure in Asia [22,23].

Tissue sarcocysts of unknown species have been observed in asymptomatic individuals from countries including Singapore, Malaysia, Thailand, India, and Uganda; the human pathogenicity of these organisms is not known [21,24-26].

Life cycle — All Sarcocystis spp have a two-host life cycle, requiring species-specific intermediate and definitive hosts (figure 1). Sporocysts excreted in the stool of a definitive host are ingested by an intermediate host; they undergo asexual development in the intestine and then the vasculature prior to forming sarcocysts in the skeletal muscle of the intermediate host. Sarcocysts in muscle are then consumed by a definitive host. Bradyzoites rupture from the sarcocyst in the gut and enter the intestinal lamina propria. Oocysts pass into the intestine and are released in stool, enabling continuation of the life cycle [5].

Humans are definitive hosts for S. hominis and S. suihominis, which are acquired via consumption of sarcocysts in undercooked beef or pork, respectively. These organisms cause intestinal sarcocystosis in humans. Snakes are definitive hosts for S. nesbitti; monkeys are postulated as intermediate hosts [27-30]. Humans can be dead-end intermediate hosts for S. nesbitti, which is likely acquired via consumption of food or water contaminated with oocysts from snakes [14]. S. nesbitti has been identified in water tank and river water samples and Sarcocystis spp from seawater from Tioman Island, Malaysia [31,32]. This organism causes muscular sarcocystosis in humans. More than 150 cases of muscular sarcocystosis occurred in Malaysia in 2011 to 2012; these likely followed consumption of food or water contaminated with the feces of the definitive host [14,15].

PATHOGENESIS — Most cases of human muscular sarcocystosis have occurred in immunocompetent individuals with minimal comorbidities. It is likely that individuals in endemic areas with repeated low-level exposure to Sarcocystis spp develop some degree of immunity, resulting in subclinical disease or presentation with attenuated symptoms. As an example, an autopsy series in Malaysia noted the presence of sarcocysts in human skeletal muscle in 21 percent of cases, suggesting frequent exposure to sarcocysts [24].

In the point-source outbreak in Malaysia that involved both Malaysians and non-Malaysians, the duration of symptoms was significantly longer and the presence of moderate to severe disease was more common among non-Malaysians despite apparently similar exposures [14]. In the cluster outbreaks, the attack rate was 60 to 97 percent [13,14]. The effect of the ingested inoculum on clinical presentation is uncertain.

CLINICAL MANIFESTATIONS — Two distinct clinical syndromes may occur in humans: intestinal sarcocystosis or muscular sarcocystosis.

Intestinal sarcocystosis — The incubation period for intestinal sarcocystosis is normally one to two days, though incubation periods as short as three hours and as long as one week have been reported [5,9]. Clinical manifestations may include nausea, vomiting, abdominal pain, bloating, and watery diarrhea. Symptoms are normally self-limited and resolve by 36 hours; few cases of prolonged diarrhea attributable to sarcocystosis have been reported [5,9,11].

Muscular sarcocystosis — The incubation period for muscular sarcocystosis is typically 9 to 13 days [14]. Symptoms last for a median of 17 days but may be prolonged for months; symptom duration of up to five years has been reported [13-15,33,34]. Early manifestations may be nonspecific and include fever, myalgia, and headache. In case clusters from Malaysia, the reported frequency of the most common symptoms was as follows: fever (82 to 94 percent), myalgia (91 to 100 percent), headache (59 to 97 percent), cough (18 to 40 percent), and joint pain (29 to 39 percent) [14,29]. Other reported symptoms include diarrhea, nausea and vomiting (particularly in the earliest days of illness), and bronchospasm [13,14]. Temperatures may be elevated to more than 39°C and be associated with rigors.

For some individuals, the manifestations may be short and self-limited, with myalgia lasting for less than one week in one-quarter of infected persons [14]. For those with more prolonged symptoms, a relapsing-remitting course is common; this can help differentiate sarcocystosis from other tropical diseases. In one prospective series, more than half of patients had greater than two episodes of clinical symptoms, predominantly fever and myalgia; episodes of relapse and remission lasted four to five days [14].

In a retrospective case series among returned travelers, the course of the illness was reported as biphasic; this observation was based on patient recollection weeks or months after disease onset in the absence of sequential clinic visits [15]. In that series, enrollment required both myalgia and eosinophilia; therefore, ascertainment of clinical findings was restricted to a subset of more severely infected patients with a more prolonged clinical course [15].

In the majority of cases, myalgia is associated with myositis, and muscle tenderness has been reported in 73 percent of cases [15]. Visible muscle swelling has been noted in up to 15 percent of symptomatic individuals; the muscles of mastication, calf muscles, and superficial back muscles are disproportionately involved [14]. There is visible swelling of the muscles of mastication approximately five weeks after exposure in up to 10 percent of cases (picture 1) [14]. Subcutaneous nodules have been reported in a number of cases [13,15,18,21]. Urticaria has also been reported and alopecia in individuals months after the initial illness [35,36].

Laboratory findings — Eosinophilia and lymphocytosis can occur but are not an absolute requirement for considering or establishing the diagnosis; these are variable depending on the phase of illness. In the first two weeks following the onset of symptoms, mild eosinophilia (less than twice the upper limit of normal) is observed in approximately one-third of cases. After the first two weeks of illness, mild eosinophilia is observed in approximately two-thirds of cases [14]. Approximately four weeks after exposure, moderate eosinophilia (1800 to 3300 eosinophils/microL) has been reported in some cases [13-15]. Absence of eosinophilia has been observed in some heavily parasitized biopsy-proven cases, particularly early in disease [14].

In the first two weeks of illness, mild lymphocytosis (≤5.0 x 10⁹/L) occurs in approximately one-third of cases. Later in the course of illness, lymphocytosis occurs in approximately two-thirds of cases [14]. Anemia and thrombocytopenia have not been reported.

Liver function test abnormalities occur; in the first two weeks of illness, increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) occur in 60 to 70 percent of patients [14]. More than two weeks after the onset of illness, these enzymes are elevated in 40 to 50 percent of patients. In general, the AST and ALT are less than twice the upper limit of normal, and the GGT is less than three times the upper limit of normal.

Serum creatine phosphokinase (CPK) is elevated in 15 percent of cases during the first two weeks of illness; this is the clinical stage prior to the formation of sarcocysts in muscle. More than two weeks after the onset of symptoms, CPK is elevated in 90 percent of cases [14]. In biopsy-proven cases, CPK is most commonly elevated in the range of 200 to 900 IU/L, with two reports of CPK up to 1400 IU/L [13-15].

DIAGNOSIS

Intestinal sarcocystosis — Intestinal sarcocystosis is diagnosed by the detection of individual sporocysts or oocysts containing two sporocysts in stool [5]. However, the prepatent period is at least 11 days; therefore, oocysts are not detected at the time of clinical illness [37]. A variety of fecal examination methods have been used including modified Kato, thick smears, flotation techniques, formalin/ethyl acetate concentrates, unstained wet mounts, and ultraviolet microscopy [9,37]. Oocysts may not take up Ziehl-Neelsen stain.

Muscular sarcocystosis — When present, a relapsing-remitting illness and facial swelling with myositis of the muscles of mastication on imaging should raise the suspicion of infection with Sarcocystis spp. Myositis may be observed with magnetic resonance imaging (MRI), particularly T2-weighted short tau inversion recovery (STIR) sequences (image 1) [14,34,36]. A presumptive diagnosis of muscular sarcocystosis can be made in the setting of compatible epidemiology, inflammation, laboratory abnormalities, and negative testing for other causes of myositis. (See 'Laboratory findings' above and 'Differential diagnosis' below.)

Definitive diagnosis is established via identification of sarcocysts in muscle tissue. Ideally, biopsy specimens are obtained under MRI guidance; alternatively, clinically affected areas may be sampled. Findings on histologic examination (hematoxylin and eosin–stained muscle sections) are variable. Cyst dimensions range from 20 to 500 microns, with a characteristic thin membrane (approximately 55 nm thick) (picture 2 and picture 3) [24,38,39]. Considerable variability may be seen in the structure of the cyst wall [5]. Characteristic "banana-shaped" merozoites may be found compartmentalized within cysts. In general, there is minimal inflammatory change adjacent to cysts [14,15,18].

Biopsy tissue may demonstrate myositis only; visible sarcocysts are typically scattered within inflamed tissue [15]. Typically, surrounding inflammation within the endomysium and perimysium occurs; it is predominantly perivascular. The severity ranges from occasional foci of predominantly lymphohistiocytic infiltrate to more widespread foci of mixed inflammation.

Polymerase chain reaction (PCR) has been used to detect S. nesbitti in human muscle. However, tissue with visible sarcocysts has tested negative by PCR. Direct 18S rDNA sequencing and nested PCR have also been used in the identification of S. nesbitti from human muscle [6,14,29]. Primers targeting 28S rRNA may improve species identification in environmental samples [32,40].

Serology is not yet a reliable diagnostic tool [14,15].

DIFFERENTIAL DIAGNOSIS — The early clinical features of muscular sarcocystosis, predominantly fever and myalgia, are nonspecific and raise the possibility of other tropical diseases including dengue, chikungunya, leptospirosis, and rickettsial disease. The differential for established myositis includes viral myositis, trichinellosis, toxoplasmosis, and toxocariasis:

●Dengue – Clinical manifestations of dengue include fever, myalgia, headache, and retroorbital pain. Laboratory findings include leukopenia, thrombocytopenia, and liver function test abnormalities. The diagnosis is established via serology. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

●Chikungunya – Clinical manifestations of chikungunya include fever, arthralgia, myalgia, and headache. Laboratory abnormalities include cytopenia and elevated liver enzymes. The diagnosis is established via serology. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

●Leptospirosis – Clinical manifestations of leptospirosis include fever, rigors, myalgia, headache and conjunctival suffusion. Laboratory abnormalities include cytopenia, elevated liver enzymes, elevated creatine kinase, and hyponatremia. The diagnosis is established via serology. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Rickettsial disease – Clinical manifestations of rickettsial disease include fever, headache, malaise, myalgia, arthralgia, and rash. The diagnosis is established via serology. (See "Other spotted fever group rickettsial infections".)

●Viral myositis – Viral myositis occurs as a complication of viral infection; clinical manifestations include fever, myalgia, and anorexia followed by rhabdomyolysis. Extreme elevations of creatine kinase may be observed. The diagnosis is established clinically. (See "Overview of viral myositis".)

●Trichinellosis – Clinical manifestations of trichinellosis include periorbital edema, muscle pain, tenderness, swelling, and weakness; they may occur as part of a suspected outbreak and/or in association with eating undercooked pork. When eosinophilia is present, it is generally marked (20 to 90 percent). The diagnosis is confirmed by serology. (See "Trichinellosis".)

●Toxoplasmosis – Toxoplasmosis gondii forms tissue cysts in skeletal muscle, myocardium, brain, and eyes. Lymphocytosis and elevated transaminases may be observed. The diagnosis is established via serology and/or biopsy. (See "Toxoplasmosis in patients with HIV".)

●Toxocariasis – Following ingestion of Toxocara canis eggs, larvae penetrate the intestinal wall and are carried by the circulation to a variety of tissues (liver, heart, lungs, brain, muscle, eyes) where they can cause severe local reactions. Marked leukocytosis with eosinophilia may be observed. The diagnosis is established via serology. (See "Toxocariasis: Visceral and ocular larva migrans".)

TREATMENT — Gastrointestinal disease is normally self-limited and does not require specific treatment.

The optimal approach to treatment of muscular sarcocystosis is uncertain. Treatment with anticoccidial agents such as trimethoprim-sulfamethoxazole, clindamycin, and pyrimethamine have been used [14,22,33]. Albendazole, corticosteroids, and methotrexate have been used with varying reports of symptom amelioration but without definite clinical improvement in many cases [13,15,23,34,36,41]. The lack of inflammation that has been noted in association with sarcocysts may limit the effectiveness of corticosteroids.

In the absence of clinical trial data, we favor supportive care and treatment with trimethoprim-sulfamethoxazole 160/800 mg two tablets orally twice daily for 14 days.

PREVENTION — Prevention of intestinal sarcocystosis consists of ensuring that beef or pork has been thoroughly cooked or frozen to kill the bradyzoites in muscle [11].

Prevention of muscular sarcocystosis entails avoidance of consumption of sporocysts of Sarcocystis spp; drinking only boiled or bottled water is the primary preventative method [11,14]. Filters capable of removing bacteria from water are also effective in removing sporocysts, but chemical disinfection is not an effective sterilization method [11]. To reduce the risk of consuming food contaminated with sporocysts, all food should be cooked thoroughly [11,14].

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Sarcocystosis is a zoonotic infection caused by a protozoan parasite of the genus Sarcocystis. Two distinct clinical syndromes occur in humans: intestinal sarcocystosis and muscular sarcocystosis. Most cases reported in the literature have occurred as part of outbreaks or case series originating from Malaysia. (See 'Introduction' above and 'Epidemiology' above.)

●Life cycle – Sarcocystis spp have a two-host life cycle, requiring species-specific intermediate and definitive hosts (figure 1). Humans are definitive hosts for S. hominis and S. suihominis, which are acquired via consumption of sarcocysts in undercooked beef or pork, respectively. These organisms cause intestinal sarcocystosis in humans. Humans are dead-end intermediate hosts for S. nesbitti, which is acquired via consumption of food or water contaminated with oocysts from snakes, the definitive host. This organism causes muscular sarcocystosis in humans. (See 'Life cycle' above.)

●Clinical manifestations

•Intestinal sarcocystosis – The incubation period for intestinal sarcocystosis is normally one to two days, though incubation periods as short as three hours and as long as one week have been reported. Clinical manifestations may include nausea, vomiting, abdominal pain, bloating, and watery diarrhea. Symptoms normally resolve by 36 hours. The diagnosis is established by detection of individual sporocysts or oocysts containing two sporocysts in stool. However, oocysts are not detectable at the time of clinical illness. Intestinal sarcocystosis is normally self-limited and does not require specific treatment. (See 'Intestinal sarcocystosis' above.)

•Muscular sarcocystosis – The incubation period for muscular sarcocystosis is typically 9 to 13 days. Early manifestations may be nonspecific and include fever, myalgia, and headache. In the majority of cases, myalgia is associated with myositis. Visible muscle swelling occurs in up to 15 percent of symptomatic individuals; the muscles of mastication, calf muscles, and superficial back muscles are disproportionately involved. The manifestations may be self-limited but associated with a relapsing-remitting course. Laboratory findings include eosinophilia, lymphocytosis, liver function test abnormalities, and elevated serum creatine phosphokinase. (See 'Muscular sarcocystosis' above.)

●Diagnosis – A presumptive diagnosis of muscular sarcocystosis can be made in the setting of compatible epidemiology, inflammation, laboratory findings as outlined above, and negative testing for other causes of myositis. Myositis may be observed with magnetic resonance imaging (MRI). Definitive diagnosis is established via identification of sarcocysts in muscle tissue. (See 'Diagnosis' above.)

●Treatment – The optimal approach to treatment of muscular sarcocystosis is uncertain; we suggest treatment with trimethoprim-sulfamethoxazole (Grade 2C). (See 'Treatment' above.)