Cryptosporidiosis

Cryptosporidiosis

I. What every physician needs to know.

Cryptosporidiosis is caused by an intracellular protozoan parasite, provoking illness in a wide host range with variable severity and affecting both immunocompetent and immunocompromised hosts, the latter are predisposed to a potentially life-threatening disease and higher risk of extra-intestinal complications. Cryptosporidium genus has at least 20 recognized species, with C. parvum and C. hominis being the most common species affecting humans.

This organism infects the gastrointestinal epithelium to produce watery diarrhea. Humans acquire the infection when ingesting cryptosporidium oocysts. Once ingested, these oocyst excyst in the gastrointestinal tract releasing infective sporozoites which will parasite the host cell after being internalized and becoming intracellular but extracytoplasmic.

This sporozoite then matures into a schizogony, through asexual reproduction, to produce merozoites. Merozoites will be released into the intestinal lumen where they can either infect new cells or undergo sexual reproduction through maturation into gametocytes. Gametocytes will produce new thin walled oocysts that can either be excreted with feces or release more sporozoites to infect new cells. Life cycle is repeated in the intestinal lumen leading to autoinfection and heavy persistent infections, with massive shedding of oocysts in the feces.

Cryptosporidiosis is a significant public health concern as oocysts are resistant to disinfectants and to conventional water treatments, there is no effective treatment, low infective dose (10-100 oocysts), there is person-person transmission (fecal-oral way) and is a big contributor to malnutrition in children in developing countries.

II. Diagnostic Confirmation: Are you sure your patient has Cryptosporidiosis?

Watery diarrhea and cramping abdominal pain, with an average duration of 2 weeks.

A. History Part I: Pattern Recognition:

Cryptosporidiosis clinical features will vary depending on host’s immunological status. Although infection can be asymptomatic, most patients will develop watery diarrhea containing mucus but rarely blood or leukocytes, and is associated with intestinal malabsorption.

Cryptosporidiosis in immune-competent individuals usually presents as one of the following scenarios: asymptomatic carriage, acute or persistent diarrhea both of which are self-limited. Incubation period is 7 to 10 days and approximately 90% of infected persons will develop symptoms after this period, lasting an average of 2 weeks (acute diarrhea) and usually not more than 2.5 months (persistent). Most patients will have diarrhea (93%) with an average of 10 watery stools per day, cramping abdominal pain (83%), fever (50-60%), nausea and vomiting (approximately 50%), and weight loss (75%).

Cryptosporidiosis in immune-compromised (AIDS, chemotherapy, immune-suppression secondary to transplant, malnutrition) patients have a wider spectrum of disease. The most common patterns of disease include: asymptomatic infection (4%), transient/sub acute diarrhea (29%), chronic diarrhea (60%), fulminant diarrhea (8%). Sub acute diarrhea usually persists for less than 2 months with complete resolution of symptoms; nevertheless, the most common presentation is chronic diarrhea with symptoms lasting more than 2 months and patients becoming much debilitated. The fulminant form of cryptosporidiosis occurs only in patients with very low CD4 count, less than 50 per cubic milliliter, and patients have an average of over 2 liters of watery stool per day.

Up to 26% of AIDS patients not undergoing highly active antiretroviral therapy (HAART) with cryptosporidial infection will develop extra intestinal manifestations, with biliary tract being the most common non-enteric site. Involvements of middle ear, pancreas, liver, stomach and lung have also been described. Reactive arthritis has been described as a complication of cryptosporidiosis in immuno-competent persons.

Biliary cryptosporidiosis, often presents with right upper quadrant (RUQ) pain, nausea, vomiting, fever, and elevated alkaline phosphatase levels. There are three distinct endoscopic retrograde cholangiopancreatographic (ERCP) patterns with papillary stenosis plus intrahepatic sclerosing cholangitis being the most common (60%), followed by papillary stenosis alone and sclerosing cholangitis alone.

B. History Part 2: Prevalence:

• Cryptosporidiosis has been described worldwide, but children and AIDS patients are at significantly higher risk, especially in resource-poor settings.

• In immune-competent adults, cryptosporidiosis accounts for 2.2% (0.2-22%) of diarrhea in developed countries and 6.1% (1.4-41%) in developing countries.

• Seven percent of children in developed countries are affected by cryptosporidial infection, and the number goes up to 12% in developing countries.

• Amongst patients with AIDS and diarrhea living in developed countries, 14% (6-70%) of cases are caused by cryptosporidium spp. and up to 24% (9-48%) of patients are with AIDS and diarrhea living in developing countries.

C. History Part 3: Competing diagnoses that can mimic Cryptosporidiosis.

Differential diagnoses for enteric cryptosporidiosis, particularly in HIV patients include many other causes of diarrhea. Some are easily identified such as bacteria Shigella, Salmonella, Campylobacter, Clostridium difficile; parasites Giardia lamblia, Isospora belli, Cyclospora cayetanesis, Entamoeba hystolytica. Other pathogens, however, can be difficult to exclude such as Mycobacterium avium, Microspora, cytomegalovirus and other viral diarrheal illnesses.

D. Physical Examination Findings.

There are no characteristic physical exam findings. The hallmark of cryptosporidiosis is diarrhea, which usually develops 6-7 days after exposure, with or without cramping abdominal pain. It may be intermittent and scant, or continuous, as well as watery and voluminous (as much as 12-17 liters/ day).

Severity and duration of the illness varies among individuals and correlation to immune status has been described.

Symptoms associated with diarrhea include low grade fever, malaise, fatigue, weakness, nausea, vomiting, and anorexia. Also note that patients with biliary cryptosporidiosis may mimic acute cholecystitis.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Even though traditionally used microscopy–based diagnosis of Cryptosporidium spp. underestimates the true burden of disease, it still is the preferred method in most microbiology laboratories. A modified Ziehl-Neelsen acid-based staining method, with or without fecal concentration, is used to identify oocysts in stool. Due to intermittent shedding of oocysts multiple stool samples may be needed.

Antibody based detection systems may be used in settings where occcysts are few.

No serum tests are necessary, nevertheless liver function tests or lipase may be abnormal if biliary tract, liver or pancreas are affected.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Intestinal biopsy through colonoscopy or enteroscopy may be needed in HIV/AIDS patients if diagnosis is still suspected despite negative stool studies or if co-infection with other opportunistic pathogens (i.e: CMV, HSV, MAC, mycobacteria, etc.) needs to be excluded.

Abdominal ultrasound may show enlarged gallbladder with thickened wall, dilated or irregular intra or extra-hepatic biliary ducts, and a normal or stenotic common bile duct in the setting of gallbladder infection.

ERCP may be required for diagnosis and treatment of cryptosporidial cholangitis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Routine “Ova plus Parasite “examination in stool does not include test for cryptosporidium, and it needs to be specifically ordered.

Serologic tests are of limited value as many healthy people have presence of cryptosporidium antibodies in serum.

III. Default Management.

A. Immediate management.

Supportive management including rehydration therapy, electrolyte replacement and antimotility agents are the main treatment strategies.

The role of antiparasitic treatment in cryptosporidiosis is unclear as is usually a self-limited infection in immuno-competent persons. Furthermore, most medications are at best partially effective in immuno-suppressed patients. Data on nitazoxanide, paromomycin, and rifamycin derivatives among severely immuno-suppresed individuals does not support the use of these medications in this patient’s population. However, most AIDS patients will improve after initiation of HAART, as it will improve immune status and, indirect evidence suggests that protease inhibitors may inhibit C. parvum cell invasion

Nitazoxanide has been used to treat cryptosporidiosis in immune-competent patients, with greater impact in malnourished children.

Nitazoxamide (Alinia) is an oral suspension and the recommended dose for adults is 500mg every 12 hours to complete 3 days of treatment.

B. Physical Examination Tips to Guide Management.

If severe dehydration occurs, intravenous fluid resuscitation may be needed.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

No laboratory tests are necessary if there is clinical improvement.

D. Long-term management.

NA

E. Common Pitfalls and Side-Effects of Management

As described above, there is no effective treatment. Side effects from the use of nitazoxanide include abdominal pain, headaches, nausea and diarrhea.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Caution has been advised with the use of nitazoxanide in patients with renal impairment however no dose adjustments have been recommended.

B. Liver Insufficiency.

Caution has been advised with the use of nitazoxanide in patients with liver impairment however no dose adjustments have been recommended.

C. Systolic and Diastolic Heart Failure

No significant changes in management. Close clinical monitoring is advised during fluid resuscitation.

D. Coronary Artery Disease or Peripheral Vascular Disease

No significant changes in management.

E. Diabetes or other Endocrine issues

No significant changes in management.

F. Malignancy

No significant changes in management.

G. Immunosuppression (HIV, chronic steroids, etc).

In HIV/AIDS patients, advice is to initiate HARRT therapy as soon as possible. Not enough evidence is available to support the use of anti-parasitic drugs in chemotherapy or transplant related immune-suppressed patients; nonetheless, most case reports describe treatment with nitazoxanide.

H. Primary Lung Disease (COPD, Asthma, ILD)

No significant change in management.

I. Gastrointestinal or Nutrition Issues

Enteric or biliary cryptosporidial infection may worsen an underlying GI pathology. Biopsy may be needed to further establish diagnosis. Nutritional support is extremely important as C. parvum is known to cause malabsorption syndrome.

J. Hematologic or Coagulation Issues

No significant change in management.

K. Dementia or Psychiatric Illness/Treatment

No significant change in management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Remind cross cover physicians that this diarrheal disease could potentially be life-threatening and will need aggressive fluid resuscitation. Intake and output monitoring every 4 hours would be appropriate.

B. Anticipated Length of Stay.

As there is no reliable palliative or curative treatment, length of stay is variable among individuals and their need to receive intravenous fluid resuscitation.

C. When is the Patient Ready for Discharge.

Whenever a patient is able to tolerate oral medications and fluid resuscitation, and has been clinically stable for at least 24 hours.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

If patient has been diagnosed with HIV/AIDS, then he should have follow-up arranged with an HIV clinic.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

Cryptosporidiosis is usually a self-limited illness or often improved after initiation with HAART (in HIV patients).

F. Prognosis and Patient Counseling.

Prognosis will vary with immune status as described above. Counseling is focused on prevention. Enteric precautions and good hygiene are essential to prevent transmission and re-infection. Patients are to avoid drinking water from rivers or lakes and use water filters that remove particles. One micron or less labeled as absolute.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

There is no JHACO core measures associated with cryptosporidiosis. However, while patient is hospitalized, hand hygiene should be achieved by HAND WASHING as oocysts are resistant to most disinfectants. Proper disposal of contaminated material is equally important to prevent transmission through fecal-oral way.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

HIV/AIDS patients should be counseled on proper use of HAART as well as ways to prevent re-infection (see above).

What's the evidence?

Tzipori, S, Widmer, G. “A hundred-year retrospective on cryptosporidiosis”. Trends in Parasitology. vol. 24. 2008. pp. 184-189.

Abubakar, I, Aliyu, SH, Arumugam, C, Usman, NK, Hunter, PR. “Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis”. Br J Clin Pharmacol. vol. 63. 2007. pp. 387-393.

Xian-Ming, Chen, Keithly, JS, Paya, CV, LaRusso, NF. “Cryptosporidiosis”. N engl J Med. vol. 346. 2002. pp. 1723-1731.

Cabana, MM, White, AC. “Treatment of cryptosporidiosis: do we know what we think we know”. Curr Op in Inf Dis. vol. 23. 2010. pp. 494-499.

Abubakar, II, Aliyu, SH, Arumugan, C, Hunter, P, Usman, N. “Prevention and treatment of cryptosporidiosis in immunocompromised patients”. Cochrane Databaseof Systematic Reviews. pp. CD004932

Legrand, F, Grenouillet, F, Larosa, F, Dalle, F, Saas, P, Millon, L, Deconinck, E, Rohrlich, PS. “Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: a prospective single center study”. Bone Marrow Transpl. vol. 46. 2011. pp. 858-62.

Mandell, G, Bennet, J, Dolin, R. “Principles and Practice of Infectious Diseases”. 2010.

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