Cryptosporidiosis

Definition

Cryptosporidiosis is the disease in humans and animals caused by protozoal parasites of the genus Cryptosporidium (phylum Apicomplexa). Cryptosporidium spp are major waterborne parasites worldwide, and more than 20 species have been documented to infect humans.

The Pathogen

The family Cryptosporidiidae has a hidden sporocyst and undergoes monoxenous completion of its cycle in one host, where it can cause predominantly intestinal, cloacal, and gastric infections. The life cycle begins with ingestion of Cryptosporidium oocysts (2 to 5 µm) by the vertebrate host, with subsequent excystation within the lumen of the small intestine to release four sporozoites ( Fig. 321-1 ). Polarized sporozoites cells harbor the apical secretory organelles typical for Apicomplexa species, including micronemes, dense granules, and a single rhoptry. The sporozoites move probably by using the canonical glideosome, which is dependent on actin and myosin, and attach to and enter the host’s epithelial cells to form intracellular but extracytoplasmic parasitophorous vacuoles, where they develop into trophozoites and subsequently type 1 meronts (schizonts). This interface suggests that the Cryptosporidium is dependent on the host’s metabolism. The parasite uses glycolysis fermentation as its sole source of energy. By asexual nuclear division, schizonts multiply and release six to eight type 1 merozoites that invade neighboring host cells and develop into type 2 meronts, or trophozoites, to complete the asexual reproductive cycle. Type 2 meronts undergo two nuclear divisions and release four type 2 merozoites that can infect the host’s cells and further develop into male (microgamont) or female (macrogamete) forms. Microgametes released from the microgamont can penetrate the macrogametes to form zygotes. Approximately 20% of the zygotes develop into thin-walled autoinfectious oocysts; some 80% become thick-walled oocysts, which are excreted in stool.

Epidemiology

Cryptosporidiosis is seasonal and related to precipitation and temperature fluctuations worldwide. Excystation of C. parvum increases in water temperatures up to 46° C (natural sunlight for 12 hours). Cryptosporidium spp can be found in wastewater, surface water, drinking water, reservoir water, groundwater, and swimming pool water. In the United States from 2015 to 2019, Cryptosporidium spp accounted for about 85% of nearly 3000 cases in 155 outbreaks of diarrhea associated with treated recreational water. In addition to exposure to treated recreational water, other significant outbreak exposures include contact with cattle and contact with infected persons, such as in child-care settings. Food-borne outbreaks also have been reported in association with contaminated apple cider, unpasteurized milk, chicken salad, vegetables, raw produce, and shellfish.

C. hominis and C parvum are responsible for over 90% of human infections. C. hominis is the dominant species in developing countries, whereas both C. hominis and C. parvum are the dominant species in industrialized nations. C. hominis is more commonly associated with clinical illness. Less common Cryptosporidium spp such as C. meleagridis , C. felis , C. canis , C. viatorum , and C. muris are largely seen in developing countries, and C. ubiquitum , C. cuniculus , and C. chipmunk genotype I are mainly seen in industrialized nations. C. parvum infection is associated with animal exposures, especially cattle and dogs, as well as residence in rural settings, whereas C. hominis infection is more common with daycare or child care and residence in urban settings.

The prevalence of cryptosporidiosis varies by geographic region, with the highest rates seen in children in developing countries, where it is one of the five pathogens (including norovirus, rotavirus, Campylobacter spp, and astrovirus) with the highest attributable burdens of diarrhea in the first year of life. Cryptosporidiosis causes more than 48,000 annual deaths worldwide in children under 5 years of age.

Cryptosporidiosis continues to be a significant cause of intestinal infection among individuals with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) who are not on effective antiretroviral therapy ( Chapter 358 ). In resource-sufficient settings, cryptosporidiosis has emerged as an important cause of diarrhea among HIV-negative individuals who are recipients of either solid organ or hematopoietic stem cell transplants. The incidence of cryptosporidiosis is also high among recent international travelers ( Chapter 265 ) and men who have sex with men.

Pathobiology

Cryptosporidium oocysts and sporozoites interact with host cells, in the processes of excystation, gliding motility, attachment, invasion, parasitophorous vacuole formation, intracellular maintenance, and host cell damage. Oocysts of Cryptosporidium spp use their cysteine and serine proteases and aminopeptidase for excystation in the upper part of the small bowel and release infective sporozoites that invade the mucosal epithelium and occasionally Peyer patch M cells, often extending to the terminal ileum and colon. The sporozoites secrete proteins from the apical organelles for locomotion and attachment. In immunocompromised patients, the organisms can be found throughout the gut, biliary tract, pancreas, and respiratory tract. Sporozoites and merozoites are internalized by similar invasion machinery and actin reorganization. Two classes of proteins, mucin-like glycoproteins and thrombospondin-related adhesive proteins, mediate adhesion of the parasite. The parasite uses proteases for the proteolytic processing of surface and apical complex proteins for invasion and for egress from the host cells. Entry into the host’s cell occurs within 30 seconds and is dependent on the parasite’s actomyosin cytoskeleton to enter host-derived bimembrane parasitophorous vacuoles in a unique intracellular but extracytoplasmic niche. Dense polymerized actin forms at the base fusion of the host-parasite bimembranes. Invasion of cells of the host leads to displacement of the microvillous border, villous atrophy, blunting and crypt cell hyperplasia, and marked infiltration by lymphocytes, plasma cells, and some neutrophils into the lamina propria, with apoptosis of infected cells. The intestinal epithelial barrier function is disrupted by the effects of Cryptosporidium on tight junction proteins. Upregulation of nuclear factor κB and the pro-inflammatory cascade causes secretory and mildly inflammatory diarrhea. Pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukins-1β and -8, and lactoferrin, are significantly increased and upregulate cyclooxygenase 2, which results in the synthesis of prostaglandin in the epithelial cells and production of substance P by the inflammatory cells. These processes decrease net sodium absorption and increase net chloride secretion, thereby causing the secretory diarrhea and clinical dehydration often seen with this infection.

Cryptosporidium oocysts have at least five characteristics that make this organism a common problem and that help define the potential risk for person-to-person spread and for waterborne and food-borne disease outbreaks. First, Cryptosporidium oocysts are resistant to many chemical disinfectants, such as chlorine. Second, the organism is highly infectious, with the median C. parvum infectious dose being 132 or fewer oocysts. Third, the size of the oocysts, 2 to 5 µm, allows them to pass through many conventional filters. Fourth, the monoxenous life cycle allows infectious oocysts to be excreted in large numbers in feces, from where they can easily spread. Fifth, the organism is associated with geographic, seasonal, and socioeconomic differences in its distribution.