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Case 6: Discussion - Cystoisosporiasis

Background and Epidemiology

Cystoisospora belli, formerly known as Isospora belli, is a coccidian protozoal parasite endemic to many regions of the world outside of the United States, including the Caribbean, Central and South America, Africa, and Southeast Asia[1,21]. Most cases of cystoisosporiasis in the United States involve either persons who previously lived in an endemic region or recently traveled to an endemic region. Hispanic individuals living in the United States have approximately a 3.5-fold increased risk of developing this infection when compared with Caucasians[2]. In a HIV-infected person, intestinal cystoisosporiasis lasting longer than 1 month constitutes a diagnosis of AIDS[3]. In the United States, cystoisosporiasis is the initial AIDS-defining illness in less than 1% of persons diagnosed with AIDS. The number of cases of cystoisosporiasis declined following the widespread use of trimethoprim-sulfamethoxazole (Bactrim, Septra) for Pneumocystis pneumonia prophylaxis. Although cystoisosporiasis does not frequently occur among HIV-infected persons living in the United States, it frequently causes gastrointestinal illness among HIV-infected persons in the developing world[4], as shown by recent surveys in Latin America that reported isosporiasis as the cause of 7 to 14% of all cases of infectious diarrhea[5,6].

Life Cycle and Transmission

The transmission of C. belli occurs predominantly via ingestion of food or water contaminated with human feces laden with C. belli oocysts[1,7]. Most persons infected with C. belli excrete the oocysts in the stool in the non-infectious (unsporulated or partially sporulated) form; the organism requires a developmental phase (sporulation) outside the host before it transforms into an infectious form (mature oocyst with sporozoites) (Figure 1)[1]. Although one report from a case series suggested transmission of C. belli from oral-anal contact[8], others have concluded this mode of transmission probably occurs infrequently, given the substantial time required outside the host for the oocysts to transform to an infectious form. Moreover, one study found that sexual partners of infected individuals do not have an increased risk of developing cystisosporiasis[4]. In rare circumstances, in place of (or in addition to) the normal development within the gastrointestinal tract, some sporozoites (or merozoites) leave the intestinal tract and invade extraintestinal sites, such as lymph nodes, spleen, and liver[1,9,10].

Clinical Manifestations

The three coccidian parasites that most commonly cause clinical disease in humans are C. belli, Cryptosporidium parvum, and Cyclospora spp. Cystisospora belli primarily causes gastrointestinal disease; typical symptoms include fever, watery diarrhea, nausea, vomiting, abdominal pain, dehydration, weight loss, and headache[4,11]. These symptoms often resemble those caused by infection with C. parvum and Cyclospora spp.[4]. Prior to the HIV epidemic, enteritis caused by C. belli was usually considered a self-limited disease. Among patients with AIDS, however, it typically causes chronic disease leading to weight loss and malabsorption[4]. In these patients, relapse frequently occurs in the absence of maintenance therapy[4,12]. Several reports have documented cases of extraintestinal disease, but such cases are rare[13]. Extraintestinal sites have included lymph nodes and spleen[9,10,14]. In addition, one report described an AIDS patient with acalculous cystitis associated with C. belli infection[15].

Diagnosis

Patients with cystoisosporiasis often demonstrate peripheral eosinophilia[5], bu this is a non-specific finding. The diagnosis of intestinal cystoisosporiasis requires identification of the characteristic oocysts in a stool sample. The most common techniques used on stool samples include wet mount examination, modified acid-fast stain, or Safranin stain. The Sheather sugar flotation method or the sedimentation concentration method may also be used[1,16]. To enhance the yield the stool sample should be concentrated prior to microscopic examination. For evaluation of HIV-infected persons with diarrhea, the preferred test is usually either a modified acid-fast stain or safranin stain, both of which stain the oocysts of C. belli, C. parvum and Cyclospora spp. oocysts a deep red color. The unsporulated Cystoisospora oocysts appear elliptical in shape, with one or both ends slightly tapered[1]. Staining of the early phase oocyst often shows a internal granular mass (Figure 2), or as it matures, one or two internal sporoblasts may be seen (Figure 3). The C. belli oocysts are approximately 30 by 15 um in size[1] and are distinctly larger and more oval than the C. parvum oocysts (4 to 6 um in diameter) and Cyclospora spp. oocysts (6 to 10 um in diameter) (Figure 4). The C. belli oocysts can also be visualized on wet mount samples using bright field microscopy, differential interference contrast, and UV fluorescence microscopy (Figure 5)[17]. Because fecal passage ofC. belli oocysts may be intermittent, multiple stool samples are recommended to enhance the diagnostic yield. Antigen detection testing is not commercially available. The diagnosis of extraintestinal cystoisosporiasis has historically been based on histologic findings that show tissue cysts that contain intracellular zoites[1]. More recently, molecular diagnostic methods using PCR have shown promise as a diagnostic tool for C. belli in biopsy specimens[21].

Treatment

Initial management of patients with intestinal cystoisosporiasis requires adequate rehydration and replacement of any deficient electrolytes. A 10-day course of trimethoprim-sulfamethoxazole[12] is recommended as the initial antimicrobial treatment of choice. The alternative regimens of pyrimethamine (Daraprim) or ciprofloxacin (Cipro) are reserved for those unable to take trimethoprim-sulfamethoxazole (Figure 6)[11,18,19]. In adequate data exist to support the use of other agents, such as albendazole (Albenza), nitazoxanide (Alinia), doxycycline, or spiramycin. Patients who have a CD4 count less than 200 cells/mm3 should take trimethoprim-sulfamethoxazole both for chronic maintenance therapy and for Pneumocystis pneumonia prophylaxis[17]. Patients with a CD4 count greater than 200 cells/mm3 who experience a relapse after completing treatment should re-initiate full-dose therapy and should be considered for maintenance therapy following retreatment. Anecdotal information suggests that effective antiretroviral therapy with immune reconstitution would reduce the risk of relapse or the need for secondary prophylaxis, but data are lacking. The opportunistic infections treatment guidelines recommend considering discontinuation of secondary prophylaxis in patients who sustain a CD4 count greater than 200 cells/mm3 for longer than 3 months[11].

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    Figure 1. Life Cycle of <em>Isospora</em> <em>belli</em>

    This graphic from the Centers for Disease Control shows the life cycle of Cystoisospora belli. At time of excretion, the immature oocyst usually contains one sporoblast.  After excretion, the sporoblast divides in two (the oocyst now contains two sporoblasts); the sporoblasts secrete a cyst wall, thus becoming sporocysts; and the sporocysts divide twice to produce four sporozoites each. Infection occurs by ingestion of sporocysts-containing oocysts: the sporocysts excyst in the small intestine and release their sporozoites, which invade the epithelial cells and initiate schizogony.  Upon rupture of the schizonts, the merozoites are released, invade new epithelial cells, and continue the cycle of asexual multiplication.  Trophozoites develop into schizonts which contain multiple merozoites.  After a minimum of one week, the sexual stage begins with the development of male and female gametocytes.  Fertilization results in the development of oocysts that are excreted in the stool.  Cystoisospora belli infects both humans and animals.

    Figure and figure legend reproduced and modified from: Centers for Disease Control and Prevention, Division of Parasitic Diseases.  DPDx: Laboratory identification of parasites of public health concern. Cystoisosporiasis.


    Figure 1
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    Figure 2. <em>I. belli</em> oocyst with Internal Granular Mass

    This modified acid-fast smear of a stool sample shows an C. belli oocyst with an internal granular mass (zygote).
    Slide courtesy of Carolyn Wallis, Harborview Medical Center Microbiology Laboratory.


    Figure 2
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    Figure 3. <em>I. belli</em> oocyst with Internal Sporoblast

    This modified acid-fast smear of a stool sample shows an C. belli oocyst with an internal sporoblast.
    Slide courtesy of Carolyn Wallis, Harborview Medical Center Microbiology Laboratory.


    Figure 3
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    Figure 4. Comparative Size of Coccidian Parasites

    These stool samples stained with modified acid-fast stain show Cryptosporidium sp.(left), Cyclospora cayentanensis (middle), and C. belli (right).

    Figure and figure legend reproduced and modifed from: Centers for Disease Control and Prevention, Division of Parasitic Diseases. DPDx: Laboratory identification of parasites of public health concern. Cystoisosporiasis.


    Figure 4
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    Figure 5. Wet Mount Staining Techniques for <em>I. belli</em>

    These stool sample wet mount tests show three wet mount techniques for diagnosing C. belli: bright-field microscopy (A & D); differential interference contrast (DIC) (B & E), and blue UV fluorescence microscopy (C & F).  The images on the top row (A,B, & C) show C. belli with a single internal sporoblast and the images on the bottom row (C,D,&E) show two internal sporoblasts.

    Figure and figure legend reproduced from: Centers for Disease Control and Prevention, Division of Parasitic Diseases.  DPDx: Laboratory identification of parasites of public health concern. Cystoisosoporiasis.


    Figure 5
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    Figure 6. Therapy for Intestinal Cystoisosporiasis in HIV-Infected Persons

    This table is based on recommendations in Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 6