Pediatrics

Cryptosporidiosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cryptosporidiosis? What are the typical findings for this disease?

Instruction

Clinical Presentation

Intestinal Disease:

After an incubation period of approximately 8 days after the ingestion of oocysts, patients present with a gastroenteritis-like syndrome and complain of watery diarrhea, often accompanied by abdominal cramps, low-grade fever, nausea, and vomiting. If the infection is chronic, diarrhea can be accompanied by wasting syndrome and/or malnutrition. Bloody stools are uncommon with cryptosporidiosis.

Asymptomatic infection occurs frequently. About one in every hundred young children in day care nurseries can asymptomatically carry the parasite.

Immuno-competent patients usually have self-limiting disease with a mean duration of diarrhea of 7 to 12 days. Relapses occur in over a third of cases. Immuno-compromised patients (especially patients with T-cell immune deficiency such as AIDS, patients with leukemia and those in the early stages following bone marrow transplantation) can suffer prolonged intractable diarrhea and weight loss.

Intestinal cryptosporidiosis can mimic graft versus host disease (GVHD) after allogenic hematopoietic stem cell transplantation. Diagnosis is paramount since effective control of cryptosporidiosis in this setting requires a reduction of immunosuppressive drugs and specific therapy, whereas diarrhea due to GVHD requires intensification of immunosuppression.

Extra-intestinal Disease

Extra-intestinal cryptosporidiosis, including biliary and respiratory tract involvement, has been more commonly reported among immunocompromised patients, particularly in HIV patients with CD4 counts that are less than 50 per ml.

Biliary tract involvement can present as: a) cholangitis, b) acute and chronic pancreatitis, c) sclerosing cholangitis, and e) liver cirrhosis. In severely immunocompromised patients, intestinal cryptosporidiosis can progress to cholangitis and/or pancreatitis.

Meanwhile respiratory tract involvement can present as: a) cough, and b) sinusitis. In most cases of respiratory cryptosporidiosis, other pathogens are found, particularly Mycobacterium spp.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Diagnostic Procedures

In most countries, including the United States, testing for Cryptosporidium is not always included in the routine examination of stool for ova and parasites. Clinicians caring for immunocompromised patients with diarrhea should keep cryptosporidiosis in their differential diagnosis.

The presence of cryptosporidium in stools can be determined by microscopic examination of stools using acid-fast staining and direct fluorescent antibody (DFA). The direct fluorescent antibody technique is more sensitive than acid fast staining. Immunodiagnostic assays directed at Cryptosporidium spp.antigens is currently the preferred method to identify Cryptosporidium infection.

Immunoassay (EIA) tests include microtiter-based methods and rapid immunochromatic cartridge assays. The polymerase chain reaction (PCR) offers the advantage of allowing for the specification and the subtyping of the various Cryptosporidium parasites that infect humans.

What caused this disease to develop at this time?

Instruction

Cryptosporidiosis is caused by infection with the protozoan parasite Cryptosporidium. Based in molecular amplification techniques and host range specificity, several species of Cryptosporidiumhave been described. The majority of human infections are due to C. hominis and C. parvum, although other Cryptosporidium species have been detected in humans, including C. melagridis, C. felis, C. canis, C. suis, C. muris and C. andersoni. Along with Giardia, Cryptosporidium is considered to be one of the most common cause of protozoan associated diarrhea worldwide.

Cryptosporidium infection is transmitted by the fecal-oral route and results from the ingestion of Cryptosporidium oocysts through the consumption of fecally-contaminated food or water, or through direct person to person or, less commonly, animal to person contact. Ingestion of as few as less than 30 oocysts can cause infection in healthy individuals.

The oocysts survive well in moist environments for prolonged periods of time and are resistant to the normally recommended concentrations of chlorine used in public drinking water distribution and recreational water facilities. The low infectious dose, variety in species that can infect humans and survival in the environment explains why Cryptosporidium has been frequently associated with large diarrhea outbreaks.

Excystation of ingested oocysts occurs in the small bowel and four motile sporozoites are released. Sporozoites attach and invade the luminal epithelial cells. Once internalized, the sporozoites asexually multiply and differentiate in trophozoites and type I meronts, which in turn can either repeat the asexual multiplication or become type II meronts to initiate a sexual cycle.

Four merozoites are produced by each type II meront and differentiate into either macrogamonts (ova) or microgamonts, which release microgametes (sperm) to fertilize the macrogramont to produce a zygote. The zygote differentiates into immediately infective oocyts that perpetuate the life cycle within the host or the sexual cycle can result in the shedding of large numbers of sporulated oocysts ready to infect the next susceptible host.

Cryptosporidium is increasingly becoming recognized internationally and was included in the World Health Organization's list of Neglected Diseases since 2004.

If you are able to confirm that the patient has cryptosporidiosis, what treatment should be initiated?

Treatment

Clinical and parasitological responses to treatment vary significantly with the immune status of the patient. Healthy individuals recover without pharmacologic therapy. Diarrhea can be managed with additional fluid intake to prevent dehydration. Antimotility agents, such as loperamide, can be used to provide symptomatic relief, although these agents are not consistently effective.

There is no effective therapy for cryptosporidiosis in immunocompromised individuals. There is some evidence in the literature that nitazoxanide may be of some benefit. Immunocompromised HIV-seropositive patients should be offered antiretroviral therapy and might benefit from concomitant nitazoxanide treatment: 500mg twice daily in adults and adolescents, 200mg twice daily in children aged 4 to 11 years or 100mg twice daily in children aged 3 to 1 year. Nitazoxanide is the only FDA approved medication to treat Cryptosporidiosis.

The stronger predictor for clinical cure in HIV-seropositive patients suffering from cryptosporidiosis is the initiation of antiretroviral therapy with subsequent restoration of cellular immunity. Case reports from cancer centers around the world have shown that combination therapy with nitazoxanide and azithromycin can be used to treat intestinal cryptosporidiosis in hematopoietic stem cell transplant recipient patients with some success.

There is no sufficient evidence to support the use of paromomycin or azithromycin as single therapy.

How frequent is cryptosporidiosis?

Epidemiology

Cryptosporidium is widespread geographically in the United States. It is a nationally notifiable disease since 1995 and the number of cases reported to the CDC has steadily increased since then, probably because of increased awareness and surveillance among health care practitioners.

In the United States, an estimated 748,000 cases of cryptosporidiosis occur each year. The current yearly incidence is estimated to be about 4 cases per 100,000 habitants and almost 40% of all the reported cases are reported to be outbreak-related.

Although cryptosporidium affects persons in all age groups, the majority of cases occur among children aged 1-9 years and young adults aged 30-39 years. Males are slightly more affected than females (53% versus 47%) and there is not a particular race or ethnicity predominant distribution.

In the United States, a marked seasonality for the disease exists with a tenfold increase in reported cases occurring between June to October when compared to January to March. This increase in cases is probably related to a higher exposure to recreational water during the warm months.

What complications might you expect from the disease or treatment of the disease?

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Chronic Complications

By far the most common chronic complication presented in patients suffering from cryptosporidiosis are those directly derived from chronic diarrhea and malabsorption; such as weight loss, failure to thrive and malnourishment with subsequent impaired cognitive function.

Cryptosporidiosis has also been associated with seronegative reactive arthritis and Reiter´s syndrome in children. There is also a possible link between cryptosporidiosis and post infectious irritable bowel syndrome.

How can cryptosporidiosis be prevented?

Preventive Measures

Prevention efforts should be focused on reducing the transmission of the parasite. Person to person transmission might be reduced by the use and enforcement of diarrhea exclusion policies in child care settings, improved hygiene practices and altered work assignments. Children with cryptosporidiosis should be excluded from the school or other institutional settings until 48 hours after the last diarrheal episode. Since swimming pool treatment may not adequately treat or remove oocysts, exclusion from swimming pools and other recreational water activities is desirable for 2 weeks.

It is also important that during outbreaks in the community, water should be boiled for at least 3 minutes to eliminate the risk for cryptosporidiosis.

The risk of zoonotic transmission might be reduced by reducing contact of humans with ill animals and controlling animal waste.

HIV positive individuals should be advised to wash their hands after potential contact with human and animal feces and after handling pets or other animals, having contact with soil, preparing food, before eating, and before and after sex. HIV positive individuals should be advised to avoid swimming or playing in recreational water and not to drink water directly from lakes or rivers. Also, HIV positive individuals should avoid the consumption of raw seafood, including oysters, to prevent cryptosporidiosis.

HIV-infected children should not be allowed contact with ill pets or stool from pets, particularly dogs and cats under 6 months of age; stray pets; or surfaces contaminated with human or animal stool. Direct contact with calves and lambs at farms or petting zoos should be avoided for HIV-infected children.

What is the evidence?

Evidence for therapy

Kaplan, JE, Benson, C, Holmes, KH. "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. vol. 58. 2009. pp. 1-207.

Mofenson, LM, Brady, MT, Danner, SP. "Guidelines for prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Association of the Infectious Diseases Society of America". MMWR Recomm Rep. vol. 58. 2009. pp. 50-62.

Amandi, B, Mwiya, M, Musuku, J. "Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomized controlled trial". Lancet. vol. 360. 2002. pp. 1375-80.

(This clinical trial demonstrated the efficacy of nitazoxanie in HIV-negative children suffering from cryptosporidiosis. The authors randomized 50 HIV-seronegative and 50 HIV-seropositive zambian children to receive either placebo or nitazoxanide 100mg twice daily for three days; diarrhea resolved in 58% of HIV-negative children receiving nitaxozanide while no benefit was observed among HIV-seropositive children. This initial clinical trial was followed by a second trial including HIV-seropositive only children, which again showed no benefit from receiving nitazoxanide. It is difficult to extrapolate the result of this trial to HIV-seropositive children from other parts of the world where anti-retrovirals are easily accessible.)

Rossignol, JF, Hidalgo, H, Feregrino, M. "A double blind placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico". Trans R Soc Trop Med Hyg. vol. 92. 1998. pp. 663-6.

(This was one of the first studies to demonstrate the efficacy of nitazoxanide in treating patients with cryptosporidiosis. 66 patients were randomized to receive placebo, 1000 grams or 2000 grams per day nitazoxanide. Patients were later on crossed over the other different study arms. Nitazoxanide demonstrated to be effective (63 and 67% clinical cure rates) treating cryptosporidioisis at both study doses.)

Legrand, F, Grenouillet, F, Larosa, F. "Diagnosis and treatment of digestive cryptosporidiosis in allogenic haematopoietic stem cell transplant recipients: a prospective single centre study". Bone Marrow Transplant. vol. 46. 2010. pp. 858-62.

(This is a case series report from a single cancer hospital in France. The authors reported the use of combination therapy using nitazoxanide and azithromycin in five hematopoietic stem cell transplant adult recipients suffering from cryptosporidiosis; three of them survived and had resolution of diarrhea, while two patients died from unrelated invasive fungal infection. It would be difficult to have blinded placebo-controlled trials in this particular population and although no strong evidence supports its use, combination therapy is widely used in cancer centers around the United States.)

Rossignol, JF. "Nitazoxanide in the treatment of acquired immune deficiency syndrome-related cryptosporidiosis: results of the United States compassionate use program in 365 patients". Aliment Pharmacol Ther. vol. 24. 2006. pp. 887-94.

(Dr Rossignol, director of the pharmaceutical company making nitazoxanide, reports the outcomes of more than 300 children and adult patients receiving nitazoxanide to treat cryptosporidiosis as compassionate use. All the patients were HIV-seropositive and the clinical response rate was 59%. This report combines children and adult patients, althougth not blinded placebo-controlled, it suggest that in regions of the world where antiretrovirals are widely available nitazoxanide can be used to treat intestinal cryptosporidiosis, as opposed to regions of the world where antiretrovirals are not as available, as Africa.)
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