Cystoisosporiasis 

Updated: Dec 02, 2015
Author: Venkat R Minnaganti, MD, FACP; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Cystoisosporiasis, which was previously known as isosporiasis, is an uncommon diarrheal illness caused by the protozoan Cystoisospora belli (formerly known as Isospora belli). C belli was first described by Virchow in 1860. The genus Cystoisospora is related closely to the generaCryptosporidium, Cyclospora, and Toxoplasma. However, Cystoisospora infection is not as common as infection with Cryptosporidium or Toxoplasma. The first case of human infection with C belli was described In 1915.[1] See the image below.

Oocyst of Cystoisospora belli with 2 sporoblasts. Oocyst of Cystoisospora belli with 2 sporoblasts. From the Image Library, Division of Parasitic Diseases at the National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.

Humans are the only known hosts for C belli, which has no known animal reservoir. Cystoisosporiasis has a worldwide distribution, although it is more common in tropical and subtropical climates. (See Epidemiology.)

C belli infection usually causes a mild and protracted illness unless the patient is immunocompromised. (See Clinical.) Clinical presentation may mimic those of inflammatory bowel disease and irritable bowel syndrome.

The diagnosis of cystoisosporiasis is based on a combination of clinical, epidemiological, and diagnostic tests. (See Workup.) Cystoisosporiasis is an AIDS-defining illness, so an appropriate workup for HIV infection should be performed, if necessary.

Also see Common Intestinal Parasites, a Critical Images slideshow, to help make an accurate diagnosis.

Although cystoisosporiasis is generally a self-limited infection, patients who are treated tend to improve in 2-3 days, whereas those who are not remain sick considerably longer. (See Treatment.) Immunocompetent hosts generally respond very rapidly to antiparasitic therapy. Immunocompromised hosts also respond well, though less rapidly; however, they have a high relapse rate once therapy is stopped and thus typically require indefinite prophylaxis after therapy.

Pathophysiology

C belli is ingested in contaminated food or water, and its life cycle requires a stage outside the host. After mature C belli oocysts are ingested, they liberate sporozoites (possibly in response to bile in the small intestine), which invade the enterocytes of the proximal small intestine. Here, they become trophozoites, and asexual multiplication (schizogony) produces merozoites that invade previously uninfected cells.

Shortly thereafter, a sexual multiplication cycle (sporogony) begins, generating oocysts that may pass into the environment. Outside the host, oocysts mature and become infectious 2-3 days later. The oocysts of C belli are resistant and remain viable in the environment for months.

Symptoms of isosporiasis suggest a toxin-mediated mechanism, but no toxin has been identified. In humans, extraintestinal forms of cystoisosporiasis are rare; however, they have been reported in patients with AIDS.

Etiology

The causative pathogen of cystoisosporiasis is C belli, a protozoan that belongs to the subclass Coccidia in the phylum Apicomplexa. The mode of transmission of isosporiasis is fecal-oral, ie, through food or water contaminated with human feces. In immunocompetent hosts, C belli infection causes a self-limited diarrheal illness. In individuals with immunocompromise, it may cause chronic life-threatening diarrhea and dehydration.

Exposure to contaminated food or water predisposes to this infection. Because an external stage in the environment is required for the oocysts to mature, direct person-to-person transmission is unlikely. Accordingly, isosporiasis is more common in areas with poor sanitation. The disease is also more common in patients with AIDS.

Epidemiology

United States statistics

The exact incidence of cystoisosporiasis in humans is unknown. C belli has been reported as the cause of outbreaks of diarrheal illness in daycare centers and mental institutions and has been implicated in traveler’s diarrhea in endemic areas.[2]

C belli infection is distinctly rare among immunocompetent individuals. Cystoisosporiasis is more common in persons with AIDS, 0.2-3% of whom have stools positive for C belli. However this increased prevalence has been reduced by the widespread use of Pneumocystis jiroveci pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) among patients with HIV infection.

In Los Angeles from 1985 to 1992, 1% of patients with AIDS had stools positive for C belli.[3] Infection was more common in foreign-born and Hispanic residents with AIDS (eg, those from El Salvador [7.4%] or Mexico [5.4%]) and less common in those receiving TMP-SMZ prophylaxis for Pneumocystis infection.[3]

Cystoisosporiasis has also been reported in patients with lymphoma and leukemia and recipients of renal and liver transplants.

International statistics

Endemic areas of cystoisosporiasis include Africa,[4] Australia, the Caribbean Islands, Latin America, and Southeast Asia. One study found positive examination findings in up to 15% of Haitians infected with AIDS.[5] In developing countries, 8-40% of patients with AIDS are infected.

Cystoisosporiasis is the initial AIDS-defining illness in approximately 2-3% of patients with AIDS who are from Africa. Among patients with AIDS who are from South America, 10% with chronic diarrhea have isosporiasis. In patients with AIDS who are from Haiti and Africa, 7-20% with chronic diarrhea have cystoisosporiasis.

Age-, sex- and race-related demographics

People of all ages are susceptible to C belli infection, although it tends to be more serious in infants and young children, possibly as a result of the risk of dehydration in this population. C belli can cause severe diarrhea in infants.

No gender predilection for infection has been noted, aside from the gender distribution of people with AIDS, the risk factor most commonly associated with this disease.

No racial predilection for isosporiasis has been reported, other than the racial distribution of people with AIDS. Among people with AIDS in the United States, Hispanics appear to be more at risk than blacks or whites, likely secondary to importation.

Prognosis

Prognosis is excellent with therapy (and prophylaxis, if appropriate).

In immunocompetent patients, cystoisosporiasis is usually a transient, self-limited illness but can sometimes result in a protracted diarrheal illness. Cystoisosporiasis has also been reported as a contributor to malabsorption syndrome in immunocompetent patients.[6]

In patients with AIDS, cystoisosporiasis can range in severity from a chronic and intermittent illness to a severe and life-threatening diarrheal illness.

 

Presentation

History and Physical Examination

C belli infection is most commonly observed in immunocompromised individuals or in individuals who have recently traveled to tropical areas, in people who are institutionalized, or in persons who live in poor sanitary conditions. The incubation period ranges from 3 to 14 days. Symptoms begin approximately 1 week after ingestion of the oocysts and last 2-3 weeks, with gradual improvement. Infection in people who are immunocompromised may continue indefinitely.

Symptoms and signs may include the following:

  • Profuse, watery, nonbloody, offensive-smelling diarrhea, which may contain mucus
  • Foul-smelling flatus
  • Cramping abdominal pain, vomiting (nausea and vomiting are uncommon)
  • Malaise, anorexia, weight loss
  • Low-grade fever
  • Steatorrhea in protracted cases
  • Myalgias (rare)
  • Headache (rare)

In immunocompromised individuals with severe or long-lasting disease, dehydration may be evident. Otherwise, minimal abdominal tenderness may be present.

Complications

Severe dehydration is the most common complication and almost always occurs in patients who are very young or immunocompromised. Acalculous cholecystitis has been reported in patients with AIDS. Tissue invasion and dissemination have been reported on autopsy findings in a few patients with AIDS. Colitis in patients with AIDS has been rarely reported. Reactive arthritis is rare but has been reported in immunocompromised patients.

 

DDx

Diagnostic Considerations

Clinical presentation may mimic those of gastrointestinal (GI) and other diseases. Conditions to be considered in the diagnosis of cystoisosporiasis include the following:

  • Aeromonas infection

  • Appendicitis

  • Atypical mycobacterial infection

  • Bacterial overgrowth syndrome

  • Campylobacter infection

  • Cholera

  • Clostridium difficile infection

  • Constipation

  • Crohn disease

  • Cytomegalovirus infection

  • Diverticulitis

  • Echovirus

  • Eosinophilic gastroenteritis

  • Food poisoning

  • Gastroenteritis, bacterial

  • Hemolytic-uremic syndrome

  • Hepatitis A

  • Hookworm infection

  • Hymenolepiasis

  • Intestinal enterokinase deficiency

  • Intestinal malrotation

  • Intestinal radiation injury

  • Intestinal volvulus

  • Intussusception

  • Irritable bowel syndrome

  • Kaposi sarcoma

  • Lactose intolerance

  • Lymphoma

  • Malabsorption syndromes

  • Norwalk virus

  • Peptic ulcer disease

  • Protein-losing enteropathy

  • Sarcocystis infection

  • Short bowel syndrome

  • Small-bowel obstruction

  • Soy protein intolerance

  • Sprue

  • Ulcerative colitis

  • Volvulus

  • Whipworm

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of cystoisosporiasis is based on a combination of clinical, epidemiologic, and diagnostic tests. Routine laboratory tests are not diagnostic, but peripheral eosinophilia is an important clue, seen in about one half of patients. Serologic tests for cystoisosporiasis are not available.

Because cystoisosporiasis is an AIDS-defining illness, an appropriate workup for HIV infection should be performed, if necessary.

Stool Examination

Stool examination for ova and parasites is the test of choice for cystoisosporiasis. Multiple specimens or specimen concentration increases diagnostic yield. Zinc sulfate or sugar flotation is the most sensitive stool concentration technique.

Mature oocysts measure 30 × 12 µm and have a thin translucent wall and 2 round sporocysts, each of which has 4 crescentic sporozoites. Auramine-rhodamine fluorescent, modified Kinyoun acid-fast, hematoxylin/eosin, Giemsa, and/or carbol fuchsin staining may be helpful in identifying the translucent oocysts (see the image below). Oocysts autofluoresce under ultraviolet epifluorescence illumination using a 450- to 490-nm excitation filter.

Oocyst of Cystoisospora belli with 2 sporoblasts. Oocyst of Cystoisospora belli with 2 sporoblasts. From the Image Library, Division of Parasitic Diseases at the National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.

Charcot-Leyden crystals and high fat content are often observed in stool specimens. Polymorphonuclear leukocytes (PMNs) are not observed in fecal specimens.

Studies suggest that real-time polymerase chain reaction (PCR) testing is promising for the detection of C belli in stool samples.[7]

 

Radiography

A double-contrast barium upper gastrointestinal (GI) series with small-bowel follow-through may be helpful. Nonspecific radiographic findings (eg, prominent mucosal folds, thickening of intestinal wall) may be observed.

The severity of radiographic findings seems to depend on duration of illness and to correlate with the degree of villous atrophy noted on biopsy findings (see Tissue Analysis and Histologic Findings). Short-term disease (< 1 y) seems to result in minimal or irregular thickening of mucosal folds. Long-term disease seems to correlate with markedly granular mucosal appearance with effacement of the folds.

Other Tests

String test

The Entero-Test (swallowed string test to provide a duodenal sample) may yield a positive specimen, if stool study results are negative.

Upper GI endoscopy

Upper GI endoscopy may provide useful specimens for examination, if the following test results are negative:

  • Duodenal aspirate for ova and parasite examination

  • Small bowel biopsy for histopathology

Electron microscopy

If performed as a part of workup for malabsorption, C belli may be observed with electron microscopy of tissue specimens.

Tissue Analysis and Histologic Findings

A small-bowel biopsy is not a routine test for diagnosis of cystoisosporiasis. Nonspecific findings of cystoisosporiasis observed in small-bowel biopsy specimens include mucosal atrophy, shortened villi, hypertrophic crypts, and lamina propria infiltrated with eosinophils. C belli may be observed in the cytoplasm of enterocytes with electron microscopy.

Histologic findings appear to correlate with the severity of the symptoms observed. Focal-to-widespread mucosal changes are associated with severe symptoms. In mild cases, the only findings may range from flattened villi to mild, nonspecific alterations and increased inflammatory cells in the lamina propria.

 

Treatment

Approach Considerations

In immunocompetent patients, cystoisosporiasis is a mild protracted illness. In patients with AIDS, patients with malignancy, or in patients undergoing chemotherapy, cystoisosporiasis can be debilitating or life-threatening. Hemorrhagic colitis occurs in rare cases.

Consultation with an infectious diseases specialist, a gastroenterologist, or both may be appropriate. Only patients with chronic cystoisosporiasis associated with severe dehydration should require continued inpatient care. Transfer may be required for the required specialists and/or therapeutic measures, if not available at the current institution.

Although cystoisosporiasis is generally a self-limited infection, patients who are treated tend to improve in 2-3 days, whereas those who are not treated remain sick considerably longer.

Immunocompetent hosts generally respond very rapidly to antiparasitic therapy, with symptomatic improvement within 5 days. Immunocompromised hosts also respond well, though less rapidly. However, these individuals relapse at a high rate (50% in 2 mo) once therapy is stopped. Such patients (eg, those with AIDS) may need life-long suppressive treatment with trimethoprim-sulfamethoxazole (TMP-SMZ).

Supportive Care

Care is supportive and symptomatic. Antibiotics may be administered (see Pharmacologic Therapy). Fluid replacement and correction of electrolyte imbalance are helpful. Therapy for dehydration may be the most urgent intervention required. Fluid losses may range from 2-20 L/d. Patients with severe diarrhea may require hospitalization.

No specific diet is recommended in patients with isosporiasis, but a low-protein, lactose-free diet is advised until any diarrhea has resolved.

Pharmacologic Therapy

For cystoisosporiasis, unlike many of the protozoal infections that cause similar diseases, effective therapies are available.

Cystoisosporiasis does not respond well to most antibiotics used to treat diarrhea. TMP-SMZ is the drug of choice because it is the best-studied and most readily available agent. Many patients with AIDS are already taking this agent as prophylaxis for Pneumocystis infection. One case report of isosporiasis refractory to TMP-SMZ has been described.[8]

Oral TMP-SMZ is well absorbed, even in patients with enteritis. A combination of 160 mg of TMP with 800 mg of SMZ (1 double-strength tablet PO q6h for 2-4 wk) is the preferred regimen. In patients who are intolerant to sulfonamides, pyrimethamine (50-75 mg PO q24h) with folinic acid (5-10 mg PO q24h) may be given for 2-4 weeks.

Patients with AIDS may require maintenance therapy for long-term suppression of C belli, typically in the form of 1 TMP-SMZ double-strength tablet 3 times a week. An alternative for long-term prophylaxis is pyrimethamine with sulfadiazine or sulfadoxine (eg, pyrimethamine 25 mg with sulfadoxine 500 mg 3 times a week), either of which should be accompanied by folinic acid. For patients who cannot tolerate sulfonamides, ciprofloxacin or pyrimethamine plus folinic acid may be nearly as effective for  treatment of an acute episode and for prophylaxis.

Studies have proposed the veterinary agent diclazuril as a possible drug of choice if further investigation confirms its use and safety.[9] Doxycycline, roxithromycin, and nitazoxanide[10, 11] are reported to have some efficacy, but the clinical data available are insufficient to recommend their routine use at present.

Anecdotal case reports also document improvement with albendazole, bismuth subsalicylate, furazolidone, metronidazole, and quinacrine; again, however, clinical trials are lacking.

Prevention

Cystoisosporiasis is a food-borne and water-borne illness. Consequently, the practice of hygienic measures may help in preventing transmission. It is important to avoid possible exposure to contaminated food and water insofar as is possible.

Appropriate isolation measures should be used because shedding of oocysts may last for weeks.

 

Medication

Medication Summary

Cystoisosporiasis does not respond well to most antibiotics used to treat diarrhea. Oral trimethoprim-sulfamethoxazole (TMP-SMZ) is the drug of choice. In patients who are intolerant to sulfonamides, pyrimethamine with folinic acid may be given for 2-4 weeks. Patients with AIDS may require long-term maintenance therapy with TMP-SMZ for suppression of C belli. Alternatively, pyrimethamine with sulfadoxine may be given.

Anecdotal case reports document improvement with albendazole, bismuth subsalicylate, diclazuril, furazolidone, metronidazole, and quinacrine; however, clinical trials are lacking.

Antibiotics

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

TMP-SMZ is the drug of choice because it is the best-studied and most readily available agent. An alternative for long-term prophylaxis is pyrimethamine with sulfadiazine or sulfadoxine (either of which should be accompanied by folinic acid). Studies have proposed the veterinary agent diclazuril as a possible drug of choice if further studies confirm its use and safety.

Trimethoprim-sulfamethoxazole (Bactrim DS, Septra DS)

TMP-SMZ inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. It is the drug of choice and is curative in the immunocompetent host. It can be used for treatment and then ongoing prophylaxis in the immunocompromised host.

Pyrimethamine (Daraprim)

Pyrimethamine is a folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. It is the second drug of choice and is particularly useful for those who cannot tolerate sulfonamides. It can also be used for prophylaxis when combined with sulfadiazine or sulfadoxine. Administer it with folinic acid to prevent hematologic toxicities.

Diclazuril

Diclazuril is investigational in the United States. This benzene acetonitrile derivative is a veterinary antiparasitic that has shown good safety and efficacy in a small number of studies involving a small number of humans. Clinical trials have been completed for use in patients with AIDS and cryptosporidial-related diarrhea. 

Vitamins

Class Summary

Vitamins are used to correct folic acid deficiency resulting from use of folic acid antagonists.

Leucovorin

A derivative of folic acid, which is used with folic acid antagonists such as sulfonamides and pyrimethamine.