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Case 9: Discussion- Cryptosporidiosis

Background and Epidemiology

Cryptosporidium species are intracellular, spore-forming protozoan parasites that infect the epithelium of the gastrointestinal tract[1,2,3]. Ten species of Cryptosporidium exist, with most human infections caused by C. parvum and less frequently by C. hominis and C. meleagridis[1,2]. Infection with Cryptosporidium in immunocompetent persons often results in asymptomatic or mild self-limited disease, but in HIV-infected patients, particularly those with low CD4 counts, infection may result in chronic or life-threatening diarrhea, or extra-intestinal disease[1,2,4,5,6]. In developed countries, an estimated 14% of AIDS patients with diarrhea have Cryptosporidium infection[1]. Before the widespread use of HAART, Cryptosporidium oocysts (or spores) were detected in up to 4% of HIV-infected patients in the United States[5]. More recently, infection rates in developed countries have decreased dramatically, with a contemporary incidence of cryptosporidiosis amongst AIDS patients estimated at less than 1 per 100 person-years[2].

Life Cycle and Transmission

Human infection occurs with ingestion of viable Cryptosporidium oocysts. After the oocysts are ingested, they release sporozoites, which then invade epithelial cells in the gastrointestinal tract, primarily in the small intestine (Figure 1)[1]. After entry into the epithelial cells, the sporozoites mature into trophozoites, which then reproduce in two cycles. In the asexual cycle the organism undergoes asexual reproduction (schizony), producing merozoites (type I), which are emitted into the lumen of the intestine and infect other gastrointestinal epithelial cells, thus multiplying and locally increasing the organism burden[3]. In the sexual cycle, some of the merozoites (type II) attach to epithelial cells, mature into gametocytes, which are fertilized in the intestinal tract, and then form into oocysts. The oocysts then release sporozoites that can either reinfect the intestinal epithelium and start the life cycle anew or be shed in feces, capable of infecting others[1]. The Cryptosporidium oocysts passed via feces may subsequently be transmitted by human-to-human or human-to-animal contact, or by consumption of contaminated drinking water[2,7]. Person-to-person transmission requires ingestion of as few as 10 to 100 oocysts, with transmission rates as high as 19% among household contacts of individuals with acute cryptosporidiosis[3]. Cattle and sheep are common animal reservoirs of the parasite[1].

Risk Factors

Patients at highest risk for cryptosporidiosis are those with a low CD4 count or some other source of immunosuppression[2]. Additional persons at risk for the disease include family members, sexual partners, and healthcare workers who are in contact with infected individuals[1]. A study that analyzed data from 6,913 HIV-infected patients in New Orleans from 1990 to 1998 identified three important risk factors for developing clinical infection: CD4 count less than 100 cells/mm3, prior AIDS-defining illness, and age less than 35 years[8]. In this study, the investigators found that older age protected against development of cryptosporidiosis, possibly due to protective immunity from past exposures.

Clinical Manifestations

After an incubation period of 7 to 10 days, infection of the gastrointestinal tract by Cryptosporidium impairs absorption and enhances secretion, typically leading to watery, non-bloody diarrhea[1]. The duration and severity of disease depend on the host immune response, ranging from an asymptomatic or mild self-limited illness, to chronic low-level diarrhea, to a profuse cholera-like illness[1,5]. Patients with a strong Cryptosporidium serologic response and previous exposure(s) are more likely to have asymptomatic infection, though they may still shed oocysts in feces and be contagious[5]. Patients' CD4 cell counts are a strong predictor of whether they will develop self-limited or persistent disease. In a retrospective analysis, HIV-infected patients with self-limited cryptosporidiosis had a mean CD4 count of 312 cells/mm3 compared to those with persistent infection, who had a mean CD4 count of 57 cells/mm3 (Figure 2)[4]. This same report found that 87% of patients with a CD4 count less than 140 cells/mm3 who had cryptosporidiosis developed persistent disease. Patients with fulminant infection typically have a CD4 count less than 50 cells/mm3, and these patients rarely completely clear the infection, presumably because the organism can use the biliary tree as a reservoir[1]. Fever occurs in up to one-third of patients, and abdominal cramping, nausea, weight loss, and malabsorption are common[1,2].

Extra-Intestinal Manifestations

Patients with advanced immunosuppression also have an increased risk for developing extra-intestinal disease, which usually occurs within the biliary tract, but case reports have documented infection in the lungs, stomach, pancreas, and middle ear[1]. When Cryptosporidium invades the epithelial cells of the biliary tract, the result may mimic primary sclerosing cholangitis, or lead to acalculous cholecystitis or papillary stenosis, which can cause pancreatitis[2,7]. Studies have revealed Cryptosporidium as the most commonly identified pathogen in cases of AIDS-related cholangiopathy[7]. Clinicians should consider this clinical entity in any HIV-infected patient presenting with fever, right upper quadrant abdominal pain, nausea, and vomiting.

Diagnosis

Diagnostic testing for Cryptosporidium should be performed in HIV-infected patients who develop acute diarrhea, chronic diarrhea, or biliary tract disease, especially if their CD4 count is less than 200 cells/mm3. The easiest way to confirm the diagnosis is to identify oocysts with microscopic examination of stool or tissue. Routine ova and parasite testing does not detect Cryptosporidium. The modified acid-fast stain, which stains the organism red, is the most common method used to detect Cryptosporidium on stool microscopic examination (Figure 3)[1,2]. Cryptosporidium can be differentiated from yeasts, which are similar size and shape but are not acid fast[2], and from other protozoan parasites, such as Cystoisospora (Isospora) belli and Cyclospora species, based on size (Figure 4). Patients with mild disease may require repeat stool testing due to the high false negative rates with low organism burden[2]. If modified acid fast staining is negative and clinical suspicion is high, direct immunofluorescence microscopy (Figure 5) and ELISA testing of stool have greater sensitivity and specificity[1,2]. Serologic testing of blood generally does not help in making the diagnosis, mainly because exposure to Cryptosporidium is common and healthy persons who do not have active disease may test positive[2]. Endoscopy is often normal, but patients with severe disease may have reduction of duodenal folds secondary to villous atrophy[7]. Hematoxylin and eosin stains or light microscopy may be performed from mucosal biopsies (Figure 6)[7] .If a patient demonstrates symptoms of biliary tract disease, an ultrasound is often the first test of choice, but endoscopic retrograde cholangiopancreatography (ERCP) is more sensitive[7].

General Approach to Treatment

Patients who are asymptomatic or have intact immune function generally do not require treatment for cryptosporidiosis. The primary treatment for AIDS patients with symptomatic cryptosporidiosis is to restore immune function with effective antiretroviral therapy (Figure 7 and Figure 8)[1,6,7]. Cell-mediated immunity is vital for protection against cryptosporidiosis, and in many cases, an increase in CD4 count to greater than 100 cells/mm3 may result in resolution of symptoms[2]. Patients with Cryptosporidium infection and CD4 cell counts greater than 350 likely will have a self-limited illness, but may benefit from antimicrobial therapy. Several antimicrobial agents have been studied for the treatment of cryptosporidiosis in HIV-infected patients, including nitazoxanide (Alinia), paromomycin (Humatin), and azithromycin (Zithromax). No antimicrobial agent, however, has been shown to be reliably effective against Cryptosporidium in the absence of antiretroviral therapy. When antimicrobial therapy is used in combination with antiretroviral therapy, nitazoxanide is the recommended agent[2]. Since patients with severe cryptosporidiosis typically have clinically-significant dehydration, supportive care with fluid rehydration and electrolyte repletion is an important component of therapy. Antimicrobial therapy has not been reliably effective against AIDS cholangiopathy, so if biliary disease is present, endoscopic therapy may be necessary. Specific interventions consist of sphincterotomy for papillary stenosis (which relieves cholangitis and may relieve pain, but does not improve survival), or cholecystectomy for cholecystitis (which does not clear the organism, indicating there may be a hepatic reservoir)[7].

Antimicrobial Agents

Nitazoxanide: The antimicrobial nitazoxanide is typically well tolerated with minimal drug interactions, and although good data exist for its effectiveness in immunocompetent patients with cryptosporidiosis, data in the HIV-infected population are mixed. In a compassionate use study in 2006 that used nitazoxanide 500 to 1500 mg twice daily in 365 AIDS patients for median 62 days, 59% of subjects had a sustained clinical response (sustained improvement in the patient's global assessment of gastrointestinal symptoms)[9]. A double-blind, placebo-controlled study of nitazoxanide in patients with AIDS randomized participants to nitazoxanide 500 mg twice daily, 1000 mg twice daily, or placebo for 14 days; the patients then crossed over to a different group based on random assignment. Participants who received the drug at either dose had higher rates of parasite eradication from stool samples than patients treated with placebo, and 19 of 22 patients whose stool was cleared of the parasite experienced resolution of their diarrheal symptoms (Figure 9)[10]. In contrast, a 2007 systematic review and analysis of cryptosporidiosis treatment in HIV-infected patients found that nitazoxanide without antiretroviral therapy provided minimal benefit in controlling diarrhea or in reducing oocyst clearance when compared with placebo[6]. Therefore, nitazoxanide may be used for the treatment of cryptosporidiosis, but it is not a substitute for effective antiretroviral therapy[2].

Paromomycin: Although paromomycin is not FDA-approved for the treatment of cryptosporidiosis, data from animal models suggest high-dose paromomycin has significant activity against Cryptosporidium[2]. In addition, studies have demonstrated initial response rates to be as high as 67% in humans, but frequent relapses cause long-term response rates to be as low as 33%[2]. Success rates are even lower in patients with CD4 counts less than 100 cells/mm3[2]. In one randomized controlled trial that compared paromomycin 500 mg four times daily for 21 days with placebo in 35 HIV-infected adults with a CD4 count less than or equal to 150 cells/mm3 (median 24 cells/mm3), response rates between the paromomycin and placebo arms did not show a statistically significant difference; the investigators concluded that paromomycin monotherapy was ineffective (Figure 10)[11]. Therefore, paromomycin is not recommended as monotherapy for cryptosporidiosis[2].

Azithromycin: In a small study, 13 HIV-infected patients with symptomatic cryptosporidiosis received azithromycin therapy, at doses ranging from 500 to 1500 once daily for 20 to 50 days[12]. Nine of the 13 patients had a good clinical and parasitologic response. A trial from India examined the efficacy of azithromycin (500 mg for 5 to 14 days) in 41 HIV-infected patients with Cryptosporidium infection[13]. Most of these patients, however, had asymptomatic Cryptosporidium infection. Among the 13 symptomatic patients, all had symptomatic improvement (50% reduction in baseline stool frequency with a feeling of well-being) after 5 days of azithromycin 500 mg once daily, but only 5 of the patients had clearance of Cryptosporidium oocysts from stool.

Paromomycin plus Azithromycin: A small study involving 14 patients with a CD4 counts less than or equal to 100 cells/mm3 (median 30 cells/mm3) demonstrated reduced oocyst excretion and some clinical improvement with a 28-day course of paromomycin 1g twice daily plus azithromycin 600 mg once daily followed by paromomycin alone x 12 weeks[14].

Summary Treatment Recommendations

  • The primary and preferred therapy for symptomatic cryptosporidiosis in HIV-infected patients with advanced immunosuppression is restoration of the immune system with antiretroviral therapy combined with supportive care, including rehydration and replacement of electrolytes.
  • Nitazoxanide is considered a second-line or complementary agent for severe cases when used in combination with antiretroviral therapy, and paromomycin plus azithromycin should be considered only if these fail.
  • Anti-motility agents like loperamide and tincture of opium may help to improve symptoms and rates of electrolyte loss, but are not effective treatment.
  • For patients with cryptosporidiosis-related biliary disease, expert consultation is recommended

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    Figure 1 - Life Cycle of Cryptosporidium. Figure 1
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    Figure 2 - Relationship of CD4 Cell Count and Cryptosporidiosis Disease in HIV-infected Persons. Figure 2
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    Figure 3 - Modified Acid-fast Staining of Stool Samples Showing Cryptosporidium Oocysts.Figure 3
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    Figure 4 - Oocyts in Stool Smears Stained with Modified Acid-fast Stains. Figure 4
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    Figure 5 - Immunofluorescence Microscopy for Detection of Oocysts. Figure 5
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    Figure 6 - Jejunal Biopsy Specimen Showing Cryptosporidium. Figure 6
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    Figure 7 - Therapy for Cryptosporidiosis in HIV-infected Persons. Figure 7
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    Figure 8 - IDSA Rating Scheme for Treatment Recommendations. Figure 8
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    Figure 9 -  Nitazoxanide for the Treatment of Cryptosporidiosis in Patients with AIDS. Figure 9
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    Figure 10 - Paromomycin for the Treatment of Cryptosporidiosis in Patients with AIDS. Figure 10