The protozoa Cryptosporidium parvum, Isospora belli, Cyclospora cayetanensis and Sarcocystis hominis all belong to the group of intestinal coccidial infections, which cause diarrhea. They have come into prominence in recent years due to causing severe and protracted diarrhea in AIDS or cell-mediated immune deficiency and infecting piped water supplies due to the chlorine resistance of oocysts. The opportunistic protozoal infections which affect HIV-infected patients include Cryptosporidium, Microsporidia, Cyclospora and
Isospora belli. Cryptosporidium also causes persistent diarrhea and proximal small-intestinal enteropathy in children with normal immune function.10,83
Cryptosporidiosis is transmitted by a 3-6 |im acid-fast thick-walled oocyst shed in stool which encysts in the lumen of the small bowel after ingestion and produces four sporozoites. These penetrate the microvillus border and develop into trophozoites, which cause disease and can reproduce asexually, releasing eight merozoites, which invade nearby cells and redevelop into tropho-zoites to continue the infection. The life cycle is completed by asexual reproduction of trophozoites to schizonts, which develop progressively into male microgametes or female macrogametes, combining to form zygotes and then oocysts, which pass into the stool. After ingestion of oocysts, encystation takes place in the upper small intestine and sporozoites invade the absorptive epithelial cells causing inflammation, partial villus atrophy, malabsorption and diarrhea. About 20% of oocysts are thin-walled and can autoinfect the host, which explains how a small number of ingested oocysts can cause severe disease, especially in immunocompromised patients. Fecal oocysts can survive for at least 2 days, and the incubation period from cyst ingestion to diarrhea in humans is 2-14 days. The major difference from Plasmodium species (malaria) is that Cryptosporidium completes its life cycle in a single host without the mosquito vector.
Cryptosporidium causes diarrheal disease in children of developing countries, in travelers and in immunocompromised patients; there have been waterborne outbreaks in developed countries. Transmission is from person to person and from animals to people by ingestion of fecally contaminated food or water. C. parvum infects numerous mammals, including man and cattle, and although there is a human-specific form, animal forms may also cause disease in humans. Oocysts are highly infectious, with ingestion of a median of 132 cysts found to be infectious in adult volunteers. Infected
AIDS patients excrete millions of oocysts daily. Person-to-person transmission is common, occurring in 19% of infected children and is especially common in day-care center settings. Oocysts are relatively resistant to conventional chlorination and filtering, but 1-p.m filters, heating (72°C for a minute) and freezing are effective.
Cryptosporium has been reported to occur in 6.1% of diarrheal cases vs. 1.5% of controls in developing world subjects compared to 2.2% vs. 0.2%, respectively, in the developed world. For AIDS patients, these rates increase to 24% vs. 5%, respectively, in the developing world and 14% vs. 0% in the developed world. A Peruvian periurban study found a peak cryptosporidiosis incidence of 0.42 episodes/year in 1-year-olds (mean childhood incidence of 0.20), with the rainy season and lack of toilets as risk factors.84 In Zambian periurban children, cryptosporidial infection appeared to be predominantly waterborne with a prevalence among diarrheal cases of 18%, and no association with home animals, nutritional status or parental education.85
In community studies of children in GuineaBissau, Cryptosporidium was found in 5.8-7.4% of diarrheal episodes and 2.0% without diarrhea, with peak prevalences in the early rainy season (17.6% in May), in young children (e.g. 12.6% in infants < 6 months) and with persistent diarrhea (15%).86-88 Additional risk factors were pigs and dogs in the household, prolonged storage of cooked food and male sex, but not impaired immu-nity.89 According to the authors, the epidemiology of infection was consistent with a small infective dose, airborne transmission and slow development of protective immunity. In Kuwait, C. parvum oocysts were found in 10% (51 cases) of childhood diarrhea, but more older children were affected (73% > 2 years).90 A Gambian study of 1200 children documented Cryptosporidium in 8.8% of diarrheal cases vs. 2.8% of controls (p < 0.001), with peak incidence during the rainy season and among infants (6-11 months).91 A Mexican study of 403 children with diarrhea had a 6.4% prevalence of Cryptosporidium, which was associated with young age, malnutrition and lack of breast feeding.92 A Brazilian case-control study showed that children who acquired symptomatic cryp-tosporidiosis before 1 year of age had a higher burden of subsequent diarrheal disease.93
A major waterborne cryptosporidiosis outbreak in Milwaukee, USA in 1993 increased IgG antibody responses from 15% to 82% over a 5-week period in the area served by the water treatment plant, demonstrating that C. parvum infection had been much more widespread than was previously appreciated from stool testing.94 During this outbreak, Cryptosporidium, as the sole pathogen, was identified in stools from only 23% of affected children suggesting that stool tests for Cryptosporidium were insensitive early in the course of illness.95 Although secondary transmission undoubtedly took place in child-care facilities, the presence of children with asymptomatic Cryptosporidium infections did not result in an increased risk of diarrhea.96
It is paradoxical that Cryptosporidium can produce such profound inflammatory mucosal damage without invasion. It has no known cytotoxins or enterotoxins, but some of the damage may be cytokine-mediated (TNF-a, IL-8), contributing to the malabsorption. C. parvum sporozoites produce a mucin-like surface glycoprotein which may help in parasite attachment to enterocytes.22 Animal studies have revealed that cryptosporidiosis impairs glucose-stimulated sodium absorption at the villus without affecting cyclic AMP-mediated chloride secretion by the crypt epithelium.97,98 The inflammatory response in the lamina propria does not appear to enhance active transport processes such as chloride secretion, but diarrhea is related to loss of villus epithelium and glucose-facilitated sodium transport.
Severe disease occurs in agammaglobulinemia, so humoral immunity provides important protection, but cell-mediated immunity is also important in clearing infection. An antibody response to Cryptosporidium develops in the ileal mucosa which is responsible for termination of the infec-tion.99 Interferon-y, produced by the Th1 subset of CD4 intraepithelial lymphocytes, is also important in combating cryptosporidiosis, as are TNF-a and IL-1P but without any synergistic effect.100,101 The mechanisms of action of interferon-Y in vitro are prevention of penetration of host enterocytes by the parasite and retardation of development of intracellular parasites, which were independent of nitric oxide-mediated killing of parasites, although interferon-y may also up-regulate nitric oxide synthesis in enterocytes.100
Parasite expulsion and immune-mediated entero-pathic changes appear to be mediated by T-cell function, dependent upon TNF, inducible nitric oxide synthase (iNOS) and IL-4 cytokines (Th2 responses).102,103 Thus, Th2 cytokines (e.g. IL-4) are involved in protection but may also produce a pathological response in the intestinal mucosa, which had been attributed to Th1 cytokines, and does not occur in TNF-a- and interferon-y-defi-cient subjects. Both severe intestinal inflammation with enteropathy and protective immune responses to intestinal parasites are dependent upon IL-4, but immune protection can be acquired without enteropathy.102 A neonatal mouse model of cryptosporidiosis documented increased inducible nitric oxide (NO) production with infection, which was worsened by NO inhibition and antioxidant administration, suggesting a protective role for NO.104,105 The severity of nutrient malabsorption, villus atrophy and abnormal intestinal permeability with Cryptosporidium infection in AIDS is proportional to the number of infecting organisms.106
Cryptosporidial infection causes watery diarrhea with low-grade fever, vomiting and often cramps, severe dehydration and hypokalemia. Among Aboriginal children in Darwin, it was found in the stool of 7.4% of admissions with diarrheal disease with a mean age of 12.2 (9.6-15.5) months and mean admission serum potassium level of 2.7 (2.4-3.0) mmol/l. It was associated with the most severe and prolonged mucosal damage and inflammation on permeability and NO testing, but showed less lactose intolerance than rotavirus.10 A retrospective hospital study of 109 cases in London, 92% had watery and offensive stools with blood and mucus only occasionally, 50% had persistent diarrhea (> 14 days, and 33% > 21 days), 51% had vomiting, 21% had significant abdominal pain and 23% were underweight.83 Biopsies in nine cases with prolonged diarrhea and failure to thrive showed a mild to moderate enteropathy with Cryptosporidium adhering to the villus epithelium, reduced villus height, reduced disaccharidases and increased intraepithelial lymphocytes. Key risk factors for cryptosporidiosis in this European setting were travel to a developing country and itinerant parents living in caravan sites. There have been two community growth studies in Peru and Guinea-Bissau, both suggesting an adverse long-term effect of cryptosporidiosis on growth.107,108
Cryptosporidium causes more prolonged and severe diarrhea, which may be fulminant, in immunocompromised patients. In an Italian study of HIV-infected children with cryptosporidiosis, the median duration of diarrhea was 32 days compared to only 4 days for other causes.109 It was also associated with loss of 5-30% of body weight. A Peruvian hospital case-control study found an association between C. parvum infection and malnutrition, and high nosocomial spread in the hospital context.110 In a follow-up study, they documented that a first symptomatic infection resulted in a mean (with 95% CI) of 342 g (167-517) weight deficit whereas asymptomatic infection (which was twice as common) led to a 162g (27-297) deficit during the first month of infected cases compared to uninfected non-diarrheal cases.111
Cryptosporidiosis is diagnosed by finding oocysts in stool using an acid-fast stain. This is sensitive with more than 10 000 cysts/g in diarrheal cases, but 50 times less sensitive without diarrhea. Immunofluorescent and ELISA techniques are more sensitive, and PCR may be even more sensitive for detecting low numbers of oocysts in stool specimens.92 Serological testing for cryp-tosporidial antibodies is useful for epidemiological surveys, but not for clinical diagnosis in endemic areas. A Peruvian study has questioned whether cryptosporidiosis is caused by a single species by identifying both human (in 81% of children) and zoonotic genotypes of Cryptosporidium (bovine, dog, C. meleagridis and felis) in HIV-negative children, with only duration of oocyst shedding longer in the human genotype.112
The high infectivity and ubiquitous oocysts in the environment make prevention by water, hygiene and sanitation programs very difficult, indeed impossible, in the developing world, where up to 95% of children in some areas have positive serology by the age of 2 years. Precautions for travelers include washing hands, boiling water, avoiding animals, proper cooking of food, peeling fruit and avoiding uncooked food in contact with unboiled water (e.g. salads).
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