Cryptosporidium is the second major cause of moderate to severe diarrhea in children younger than two and an important cause of mortality worldwide. It occurs most commonly during waterborne epidemics and in immunocompromised hosts. Cryptosporidiosis may be underrecognized and underdiagnosed. Additionally, treatments are suboptimum, and we do not currently have robust preventative measures. Fortunately, most infections are self-limited in immunocompetent hosts but may be associated with chronic symptoms, malnutrition, and other complications in high-risk patients.
Cryptosporidium is part of the coccidia group of protozoa, which also includes Isospora and Cyclospora. Coccidian parasites are characterized by the ability to reproduce asexually and sexually. However, in contrast to the other coccidian parasites, Cryptosporidium organisms infect only the brush border of the intestinal epithelium, as opposed to deeper tissue. Human infections have been reported in association with more than 15 species of cryptosporidium. The two main strains of Cryptosporidium that cause disease are Cryptosporidium hominis and Cryptosporidium parvum. Cryptosporidium parvum is identified more often in rural areas as it associated with cattle and other animals. Cryptosporidium hominis is more common in urban areas, as opped to rural ones. Other species less commonly associated with human disease include Cryptosporidium felis, Cryptosporidium meleagridis, Cryptosporidium canis, and Cryptosporidium muris.
Contaminated water sources or fecal-oral transfer frequently spread Cryptosporidium. A recent Centers for Disease Control and Prevention (CDC) report shows that the incidence of Cryptosporidium outbreaks has increased significantly in the United States. Many outbreaks in the United States have been associated with the contamination of recreational and municipal water supplies. Outbreaks in daycare centers have also been reported, likely due to fecal-oral transmission. Transmission during anal intercourse has also been reported due to fecal-oral transmission. Cryptosporidium is also associated with seasonal changes and malnutrition. Studies have shown that higher temperature and more rainfall are associated with an increased risk of cryptosporidiosis. The number of reported cases has increased in recent years with increasing clinical recognition and testing. It is more common in low resource settings, with 5% to 10% of immunocompetent hosts shedding the organism in low resource countries as opposed to approximately 1% in high resource settings. Animal exposure, particularly in cats and cattle, is also associated with increased risk of infection. Children and the elderly are most commonly diagnosed with cryptosporidiosis. Patients with acquired (human immunodeficiency virus, chemotherapy, immunosuppressant medications,) or congenital (hypogammaglobulinemia; IgA deficiency) immunodeficiency are at highest risk of infection and for prolonged or severe illness.
Cryptosporidium can persist in the environment as an oocyst that contains four sporozoites, which are the infectious form of the parasite. Following exposure, the incubation period ranges from two to ten days, with an average of seven days. Once ingested, the oocyst travels to the small intestine, and excystation releases the sporozoites. The sporozoites settle within the walls of the small intestine and undergo asexual multiplication within extracytoplasmic parasitophorous vacuoles. Each cell reproduces in massive quantities, producing both thick-walled oocysts that can be shed into the stool and persist in the environment. The cells also produce thin-walled oocysts that can auto-infect the patient. This auto-infection is thought to be responsible for the increase in the severity of disease seen in immunocompromised patients. Symptoms are caused by three proposed mechanisms: 1) infiltration of the lamina propria by inflammatory cells; 2) increased epithelial permeability, villous atrophy, and cell death; and 3) malabsorption due to loss of intestinal architecture. Cryptosporidium can modify the host immune response to avoid apoptosis of the infected cell, allowing for persistence of infection.
Cryptosporidiosis presents as profuse watery diarrhea and wasting due to malabsorption. It is not unusual for symptoms to be cyclical, with periods of improvement and worsening over one to two weeks. In most cases, diarrhea resolves spontaneously within seven to 14 days. Fever, nausea, and vomiting may also occur, particularly in infants. Abdominal pain is also common. Chronic diarrhea can occur in patients with immunocompromising conditions, particularly human immunodeficiency virus (HIV) infections. This may last for months to years without adequate treatment of their immunocompromising condition. In immunocompromised patients, biliary, and pulmonary complications can also occur. Complications can include malnutrition, growth delays, and cognitive impairment. Malnutrition also appears to increase the risk of infection. Cryptosporidiosis is associated with more chronic symptoms and higher mortality rates than other causes of diarrhea in childhood. In immunocompromised patients, in particular, mortality can occur in the early stages of the infection. Asymptomatic infection is also common and may also be associated with malnutrition. Studies have identified asymptomatic infection in 0% to 6% children in endemic areas.
Cryptosporidium can be diagnosed by identification of the parasite in the stool with special stains, by antigen detection assays or by nucleic acid/polymerase chain reaction (PCR) testing. On stool staining, the mature oocyst is identified using modified acid fast staining. An advantage of stool staining is the low cost of the modified acid fast reagents; however, this requires technical training to visualize the organisms appropriately. Improved diagnostic ability with PCR studies and antigen detection has increased the ability to diagnose this diarrheal pathogen. An advantage of molecular testing via PCR is that it can distinguish which species is causing symptoms. Serologic assays are also used to assess the burden of infection in populations, both symptomatic and asymptomatic.
In immunocompetent patients, nitazoxanide is the treatment of choice and FDA-approved for the treatment of cryptosporidiosis. Unfortunately, it is not always successful in reducing symptoms. Paromomycin or azithromycin may also be used. However, in immunocompromised patients, these treatments may fail without immune reconstitution. Intact cellular immunity is essential for resolution of symptoms. Drug targets under investigation include microtubule function, calcium-dependent protein kinases and other metabolic pathways key for cryptosporidiosis growth.
Currently, there is no vaccine available to prevent cryptosporidiosis. However, several approaches are under investigation including a DNA-based vaccine and several antigens. While there is a role for cellular immunity in response to cryptosporidiosis, the role of humoral immunity is not well defined. Environmental control of the pathogen is important. Interestingly, studies have shown that drinking bottled water alone does not decrease the risk of infection in endemic areas, highlighting the multiple possible avenues of environmental exposure that must be addressed. Good hand-washing and careful consideration of food and water sources are essential. Alcohol based hand sanitizers do not kill the oocysts. Importantly, cryptosporidia are resistant to typical ozone and chlorine-based water purification measures, which increases the risk of outbreaks associated with inadequately treated water supplies. Filtration is required to remove the organism from water supplies. Patients diagnosed with Cryptosporidium infections are advised to avoid swimming in public pools for at least two weeks after resolution of symptoms. Use of condoms is recommended to avoid anal-fecal transmission during intercourse.