Cryptosporidium spp. are intestinal protozoan parasites of the phylum Apicomplexa, which cause diarrheal disease in humans worldwide (reviewed in [1–6]). In immunocompetent individuals, infection with this parasite may be asymptomatic or cause a self-limiting diarrheal illness. However, in immunocompromised patients such as those with HIV/AIDS Cryptosporidium spp. may cause severe, chronic and possibly fatal diarrhea and wasting. Although Cryptosporidium was discovered in 1907, it was not till 1976 that the first human cases of cryptosporidiosis were reported and not till the onset of the AIDS epidemic in the early 1980s that this parasite became widely recognized as a human pathogen (reviewed in [4,7,8]). Indeed, cryptosporidiosis was one of the original AIDS-defining illnesses and as such was associated with an increased risk of death compared to other AIDS-defining illnesses . The use of highly active antiretroviral therapy (HAART) in the past 2 decades has reduced the prevalence of this disease in AIDS patients in industrialized countries [10–12]. However, the emergence of drug-resistant HIV variants and failure or discontinuation of HAART has been associated with re-emergence of Cryptosporidium spp. infection in these patients [13,14]. Even patients with advanced AIDS who are on HAART have recently been reported to have Cryptosporidium spp. infection . Although antiretroviral treatment (ART) has recently become available in some developing countries it is not widely available or affordable in most areas where the burden of HIV/AIDS is the greatest. In the absence of ART, HIV-infected patients are subject to a cumulative lifetime incidence of diarrhea estimated at up to 100% in developing countries  with chronic diarrhea affecting up to 76% of patients with AIDS .
In 2004, cryptosporidiosis was added to the WHO's ‘Neglected Diseases Initiative’ which includes diseases that occur mainly in developing countries and are linked to poverty and lack of access to services . In the absence of a universal treatment program and with the lack of access to care, cryptosporidiosis continues to be a major opportunistic infection and an important cause of morbidity and mortality in persons living with HIV/AIDS in developing countries. Together with the lack of effective specific treatment for cryptosporidiosis in immunocompromised patients, this underscores the critical importance of continuing efforts to develop strategies to prevent and treat this disease in vulnerable populations. Here we review the current state of knowledge about cryptosporidiosis in patients with HIV/AIDS, with a focus on studies from developing countries. In addition, since knowledge of protective immune responses is essential for developing immune-based interventions such as vaccines and immunotherapy, we review what is known about immune responses in cryptosporidiosis, focusing on recent studies.
Cryptosporidiosis is prevalent worldwide and Cryptosporidium spp. have been identified in every continent except Antarctica (reviewed in [3,19]). The prevalence of cryptosporidiosis varies widely among different geographic regions and populations at risk and depends on the diagnostic method used to identify the parasite. Seroprevalence studies suggest much higher rates of infection than reports based on detection of the parasite in the stool  and range from 30 to 89% (depending on age, geographic location and drinking water source) even in industrialized countries such as the USA [20–22]. Although prevalence rates of cryptosporidiosis have fallen in some industrialized countries such as the UK, following implementation of new drinking water regulations , in the USA, Cryptosporidium spp. infections have recently been reported to be increasing, most likely due to increased detection of recreational water outbreaks . In patients with HIV/AIDS, reported prevalence rates of cryptosporidiosis also vary widely, ranging from 0 to 100% (reviewed in ) with the higher rates reported before ART was in widespread use or from developing countries where ART is not available. However, it is not clear what proportion of the difference in estimates is contributed by differences in study design, geographical location, population group, sensitivity of laboratory methods, or stage of disease.
Most studies on cryptosporidiosis in developing countries have been carried out on HIV-infected adults and employed microscopy on modified acid fast staining of direct or concentrated stool sample preparations for diagnosis . A limited number of studies have used ELISA and PCR for detection [25,26], and found a higher sensitivity for PCR and lower for antigen detection ELISA, compared to microscopy. The data on prevalence in studies using these methods are highly varied. The wide variation in estimates could also reflect issues of study design, with prevalence rates of more than 70% coming from studies with small sample sizes, geographical differences that could affect exposure, as well as differences in the populations being studied, especially with respect to socioeconomic status and access to potable water. The high prevalence of Cryptosporidium spp. in AIDS patients in developing countries is probably related to an increased risk of acquiring infection from infected contacts and prolonged excretion, which in turn increases the risk of subsequent transmission. In patients with HIV/AIDS the risk of acquiring cryptosporidiosis is associated with the degree of immunosuppression as measured by CD4 cell counts [9,27–29] (Table 1). Other risk factors for cryptosporidiosis in patients with HIV/AIDS include sex, age, ethnicity and sexual practices [9,29–33].
Cryptosporidiosis is transmitted via the oral–fecal route either by ingestion of contaminated water or food or by direct person-to-person (anthroponotic) or animal-to-person (zoonotic) contact [3,34–37]. The infectious dose depends on the infecting strain, with as few as 10 oocysts sufficient to cause infection . Cryptosporidiosis is largely a water-borne infection and Cryptosporidium spp. have been the causative agents of numerous outbreaks of waterborne illness worldwide . Oocysts, the resilient, infectious stage of the parasite are resistant to chlorination and can survive in water, for prolonged periods of time. In industrialized countries, Cryptosporidium spp. are one of the commonest causes of water-borne outbreaks of diarrheal disease [19,34] and were the causative agents of the largest ever documented outbreak of waterborne disease in the world, which affected an estimated 403 000 people in Milwaukee, Wisconsin in 1993 . Most of the deaths related to this outbreak occurred in AIDS patients . Recently, most water-borne outbreaks of cryptosporidiosis in the USA have occurred due to contamination of recreational water sources such as swimming pools and water parks . Because of the potential for intentional contamination of water supplies, Cryptosporidium is listed as a Category B Priority Pathogen for Biodefense by the US Centers for Disease Control and the National Institutes of Health .
Clinical features, diagnosis and treatment
The clinical features of cryptosporidiosis vary widely depending on the immune status of the host (reviewed in [2,3]) (Table 2). In immunocompetent individuals many Cryptosporidium spp. infections are asymptomatic, as suggested by the high rates of seropositivity (as high as 89% in some parts of the USA ) in the general population. The incubation period for symptomatic cryptosporidiosis is 1–2 weeks and watery diarrhea is the commonest symptom, but abdominal pain, nausea, vomiting and fever may also occur. The illness is self-limited and generally resolves after 1–2 weeks. However, relapse of symptoms following an asymptomatic interval has been reported . Cryptosporidial infection in children in developing countries, particularly in those who are malnourished, often results in persistent diarrhea and may lead to growth faltering, and physical and cognitive impairment (reviewed in ).
In patients with HIV/AIDS, clinical manifestations vary with the degree of immune compromise (reviewed in [3,19,42]). Those with CD4 cell counts above 180–200/μl may be asymptomatic or develop self-limiting diarrheal illness. However, patients with advanced AIDS (CD4 cell counts <50/μl), particularly in developing countries where ART is not available, can have severe diarrhea that can persist for several months, resulting in severe dehydration, weight loss and malnutrition, extended hospitalizations, and mortality. In addition, patients with advanced AIDS are at greater risk of developing extraintestinal infection, particularly of the biliary, pancreatic and respiratory tracts (reviewed in [3,6,19]). Cryptosporidium spp. are the most commonly isolated pathogens in the biliary tract in patients with AIDS-associated cholangiopathy . Recently, respiratory cryptosporidiosis has been reported in HIV-uninfected children in Uganda, raising the possibility that this complication may occur more commonly in HIV-infected adults as well in this region . AIDS patients with cryptosporidiosis also have a significantly shorter duration of survival from the time of diagnosis .
Microscopic detection of oocysts by modified acid fast staining of stool samples (Fig. 1) remains the gold standard for clinical diagnosis of cryptosporidiosis (reviewed in [3,18]). However, this method is less sensitive, laborious, time-consuming and requires a skilled operator to distinguish oocysts from yeast and other debris. Antigen detection assays such as immunofluorescence assays and ELISA, on stool samples are used frequently and are more sensitive and specific than microscopy. However, false-positives have been reported for ELISAs . Although molecular methods such as PCR have been shown to be much more sensitive than other methods for detection of Cryptosporidium spp. in stool samples [25,47,48], these assays are not routinely used for clinical diagnosis.
In spite of almost three decades of research on evaluation of over 100 therapeutic agents (reviewed in ), nitazoxanide is the only drug that has shown some degree of anticryptosporidial efficacy and has been approved by the Food and Drug Administration for treatment of cryptosporidiosis in immunocompetent persons in the USA [50,51]. Although an intent-to-treat analysis of a compassionate use trial of nitazoxanide in AIDS patients in the US suggested clinical improvement in 59% of those enrolled, a subsequent meta-analysis of seven clinical trials of nitazoxanide indicated that this drug is not effective in immunocompromised individuals [42,52]. A recent double-blind, randomized, placebo-controlled trial of high-dose, prolonged nitazoxanide treatment in Zambian children with AIDS and cryptosporidiosis confirmed the lack of efficacy of this drug in the immunocompromised .
Initial treatment of cryptosporidiosis includes fluid and electrolyte replacement and use of antimotility agents (reviewed in [3,5]). Nitazoxanide is recommended in immunocompetent individuals  but as discussed above may not be effective in the immunocompromised. In patients with HIV/AIDS, the mainstay of treatment is immune reconstitution with combination ART (cART) which results in clearance or abrogation of infection. Since HIV protease inhibitors have some anticryptosporidial activity in vitro and in animal models [55,56], it has been suggested that cART include protease inhibitors .
Cryptospordium spp. exist in many intracellular and extracellular developmental stages (Figs 1 and 2). Infection is initiated by ingestion of oocysts either in contaminated water or food or by direct person-to-person or animal-to-person contact [1,6]. Oocysts undergo excystation in the small intestine to release sporozoites that attach to and invade the brush border membrane of intestinal epithelial cells. Replication occurs within a parasitophorus vacuole, in a unique intracellular but extracytoplasmic niche, via asexual and sexual cycles. During the asexual cycle, merozoites are released, invade adjacent cells and perpetuate this cycle or differentiate into sexual stages which fuse to form zygotes. These mature into either thick-walled oocysts that are released into the external environment, or thin-walled oocysts that rupture in the intestinal lumen releasing sporozoites that initiate a new round of replication. These thin-walled autoinfective oocysts are believed to contribute to perpetuation of the infection in patients with HIV/AIDS .
Species and subtypes
There are two major Cryptosporidium spp. which cause human infections (Table 3); C. hominis primarily infects humans and C. parvum infects humans as well as other animals (reviewed in ). Other species that may infect humans include C. wrairi, C. meleagridis, C. felis, C. saurophilum, C. baileyi, C. muris, C. andersoni, C. serpentis and C. nasorum as well as cervine and rabbit genotypes. In developing countries C. hominis is the most commonly identified species (reviewed in ).
Based on significant variation at a few polymorphic loci, Cryptosporidium spp. have been further classified into subtypes . The most commonly used tool for subtyping is based on polymorphisms in the gene encoding gp40/15 (also called gp60), a major surface glycoprotein (reviewed in ). Although many different Cryptosporidium spp. and subtypes have been identified in patients with HIV/AIDS, particularly those from developing countries (Table 4), there is no particular predilection for infection with any particular species in these patients . However, in recent studies from India and Peru, HIV-infected patients were found to be infected with a greater diversity of species and subtypes compared to immunocompetent individuals in the general population in the community [59–62]. In addition, the clinical manifestations of cryptosporidiosis in HIV-infected patients in developing countries appear to vary depending on the infecting species or subtype. Patients with HIV/AIDS in India who were infected with zoonotic species of Cryptosporidium, were more likely to have diarrhea and fever than those infected with C. hominis . A study of HIV-infected patients from Tanzania showed that C. hominis infection was associated with a longer duration of symptoms, a higher rate of asymptomatic infection, and a lower CD4 cell count compared to C. parvum infection . In HIV-infected patients in Peru, individuals infected with C. parvum, C. canis, C. felis, and C. hominis subtype family Id were more likely to have chronic than acute diarrhea compared to those infected with other subtypes .
Although the immune status of the host plays a critical role in determining the outcome and severity of cryptosporidiosis, immune responses to Cryptosporidium spp. are still not completely understood. Much of what is known comes from studies in animal models (reviewed in [65,66]) and in experimentally infected human volunteers with a few studies in naturally infected humans (reviewed in ). Overall, these studies demonstrate that both innate and adaptive immune responses are essential for protection from and resolution of infection and that CD4+ T cells and the cytokine IFNγ are of primary importance in anticryptosporidial immune responses (Table 5).
Innate immune responses
The inherent resistance of mice to C. parvum infection can be attributed to an early IFNγ response, and even temporary neutralization of IFNγ with a neutralizing antibody renders mice susceptible to infection [65,68] severe combined immunodeficiency disease (SCID) mice develop a chronic infection 18–30 days post infection, but if IFNγ production is disrupted in this background, the mice develop an acute, overwhelming infection . Mice produce IFNγ within 24 h of C. parvum infection, from naive CD8+ intestinal intraepithelial cells (iIELs), but the signals initiating this response are unknown . SCID-beige (bg) mice that lack all immune cells except neutrophils and macrophages are resistant to acute infection  and it was shown that this protection is conferred by macrophages that have been activated by IFNγ from neutrophils. In vitro, IFNγ has been shown to render intestinal epithelial cells resistant to infection . In humans, IFNγ is detected in jejunal biopsies from individuals previously exposed to Cryptosporidium spp. but not naive individuals, suggesting a possible mechanism for the differences in resistance between humans and mice . Interestingly, C. parvum infection down-regulates IFNγ-induced protein expression in epithelial cells, possibly by suppression of signal transducer and activator of transcription (STAT) 1α signaling , In the absence of IFNγ, expression of IL-15 in the jejunal mucosa of human volunteers was associated with a reduced parasite burden  suggesting that in humans, this cytokine may be involved in IFNγ-independent control of infection via activation of innate immunity.
Toll-like receptor-mediated pathways
Like many protozoal parasites Cryptosporidium spp. activate the Toll-like receptor (TLR) pathway. In vitro, Cryptosporidium spp. infection of human cholangiocytes activates TLR signaling pathways through both TLR2 and TLR4, resulting in release of IL-8 and human β defensin-2 (HBD-2) . Inhibition of TLR2 and 4 signaling with a MyD88-dominant negative construct resulted in increased numbers of parasites in the infected cells, suggesting that the TLR signaling pathway contributes to suppression of parasitemia. Cryptosporidium spp. induction of TLR expression is associated with a reduction in the micro-RNA let-7i . These in-vitro observations are corroborated by studies showing that MyD88 knockout mice are significantly more susceptible to infection than their wild-type littermate controls .
Mannose binding lectin
Mannose binding lectin (MBL), an activator of the alternative complement pathway, also plays a role in the innate immune response to Cryptosporidium spp. . AIDS patients from Zambia were at significantly increased risk of cryptosporidiosis if they carried homozygous mutations in the MBL-2 gene , and low serum MBL levels in Haitian children were associated with Cryptosporidium spp. infections . Likewise, an increased risk for recurrent infections was associated with low serum MBL levels and MBL-2 polymorphisms in Bangladeshi children . However, MBL A/C-/- mice were not susceptible to cryptosporidiosis , suggesting that alterations in MBL levels may only contribute to susceptibility in the presence of other immune deficiencies.
Adaptive immune responses
Cellular immune responses
The importance of CD4+ T-cell-mediated immune responses in resolution of Cryptosporidium spp. infections has been clearly established. In humans, this is best illustrated by the increased susceptibility of AIDS patients to infection with this parasite and the observation that AIDS-associated cryptosporidiosis resolves with the restoration of CD4+ T cells following ART [12,13,45,83]. Studies of cryptosporidiosis in immunocompromised mouse models offer further support of this hypothesis (reviewed in [65,66]). T cells from mesenteric lymph nodes (MLNs) and spleens of infected mice, and peripheral blood mononuclear cells (PBMCs) from humans exposed to Cryptosporidium spp. proliferate and secrete cytokines upon exposure to crude preparations of C. parvum oocysts and sporozoites or recombinant proteins [84–90]. The responding cell population (when identified) is predominantly CD4+, αβ TCR+ [84,86,89]. Although not essential, CD8+ T cells, particularly in the IEL population, may also contribute to control of infection [68,91–93] CD40–CD40L interaction is also essential for clearance of C. parvum in mice and in humans [94,95]. Individuals with X-linked hyper IgM syndrome, caused by mutations in the CD40L gene, are highly susceptible to disseminated cryptosporidiosis [96,97].
Whereas IFNγ is of primary importance in resistance to and resolution of C. parvum infections in mice [90,98] complete immunity to cryptosporidiosis involves a complex balance of Th1 and Th2 cytokines [99,100]. Studies using various knockout mice have demonstrated that IL-4, IL-12, IL-18 and IL-23 all contribute to control of C. parvum infections [100–104].
In human volunteers challenged with C. parvum, expression of IFNγ and IL-4 in jejunal biopsies was associated with prior exposure to the parasite , and IFNγ expression was associated with an absence of oocyst shedding . T-cell clones responsive to Cryptosporidium spp. antigens were isolated from PBMCs of healthy individuals with prior cryptosporidiosis . All clones were CD4+ αβTCR+ CD45RO+ (memory phenotype) and exhibited hyper production of IFNγ upon antigen stimulation. Some of the T-cell clones exhibited a Th0 phenotype, secreting IL-4, IL-5 or IL-10 in addition to IFNγ. Preincubation of human intestinal epithelial cells with IFNγ in vitro significantly reduces C. parvum infection of the cells, and this effect is potentiated by IL-4 [71,105].
Humoral immune responses
The protection conferred by serum and mucosal antibody responses that arise following Cryptosporidium spp. infection is unclear. In mice, B cells are not required for resistance to, or resolution of infection . In humans, the presence of pre-existing antibodies to specific antigens correlates with resolution of infection and protection from subsequent challenge [107–109]. However, it is not clear whether the antibody responses are themselves protective or whether they are simply markers of protective cellular responses . Passive transfer of anti-C. parvum monoclonal antibodies , immune colostrum [110–112] or egg yolk antibody [113,114] can reduce infection, protect against the development of diarrhea and reduce oocyst shedding, but does not eliminate the infection.
In the pre-ART era, many attempts were made to treat AIDS-associated cryptosporidiosis with bovine colostrum with limited success [110,115–117] and a trial of hyperimmune bovine colostrum in human volunteers challenged with C. parvum had no significant effect on the course of infection though there was a trend towards less diarrhea in patients treated with colostrum . However, it is perhaps important to note that the most efficacious preparations in the animal studies were generated with individual recombinant C. parvum proteins [112,119,120]; the efficacy of such preparations in humans has not been investigated.
The immune response to cryptosporidiosis in patients with HIV/AIDS
CD4 T cells are clearly of prime importance in clearing cryptosporidiosis, therefore the susceptibility of AIDS patients to cryptosporidiosis is not surprising. There are certain aspects of the host–parasite interaction that perhaps further contribute to the particular susceptibility of AIDS patients to cryptosporidiosis (given below).
Immune responses compromised by HIV/AIDS that contribute to susceptibility to Cryptosporidium:
- Depletion of lamina propria CD4+ T cells
- Poor proliferation and altered cytokine secretion of PBMCs
- Increased CXCL10 expression in Cryptosporidium-infected intestinal epithelial cells
- Inhibition of TLR4 expression by HIV tat protein
Lamina propria CD4+ T cells are the first to be depleted in HIV , and recovery of an AIDS patient from cryptosporidiosis was associated with rapid repopulation of the mucosa with CD4+ lymphocytes . PBMCs from HIV-positive individuals with cryptosporidiosis, stimulated with C. parvum antigens, exhibit poor proliferative responses and altered cytokine production [85,123]. In AIDS patients with active cryptosporidiosis, infected epithelial cells express high levels of the chemokine, CXCL10, and expression levels correlate with the parasite burden . Upon immune reconstitution, the levels of CXCL10 declined, and intestinal CD4 T cells increased. Since CXCL10 increases the rate of HIV replication in vitro, it was suggested that elevated CXCL10 in cryptosporidiosis may contribute to HIV destruction of CD4+ T cells. Innate immune responses may also be affected. Inhibition of TLR4 expression in cholangiocytes with HIV tat protein resulted in increased parasite numbers, suggesting that this may contribute to the particular susceptibility of AIDS patients to biliary cryptosporidiosis .
Although, with the widespread use of effective ART, cryptosporidiosis is no longer the devastating illness it once was in AIDS patients in developed countries, it continues to pose a major threat to AIDS patients in resource-poor developing countries where ART is not widely available or affordable. Since there is currently no effective specific therapy or vaccine available for cryptosporidiosis in the immunocompromised, it is imperative to continue investigation into the biology of Cryptosporidium and host immune responses to it in order to develop novel and effective prophylactic and therapeutic strategies to prevent and treat this disease in those who are at the greatest risk of acquiring it and suffering its consequences.
The authors' work on Cryptosporidium and cryptosporidiosis is funded by the US National Institutes of Health.
1. Tzipori S, Ward H. Cryptosporidiosis: biology, pathogenesis and disease. Microbes Infect 2002; 4:1047–1058.
2. Leav BA, Mackay M, Ward HD. Cryptosporidium species: new insights and old challenges. Clin Infect Dis 2003; 36:903–908.
3. Huang DB, White AC. An updated review on Cryptosporidium
. Gastroenterol Clin North Am 2006; 35:291–314, viii.
4. Dillingham RA, Lima AA, Guerrant RL. Cryptosporidiosis: epidemiology and impact. Microbes Infect 2002; 4:1059–1066.
5. Collinet-Adler S, Ward HD. Cryptosporidiosis: environmental, therapeutic, and preventive challenges
. Eur J Clin Microbiol Infect Dis
6. Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med 2002; 346:1723–1731.
7. Tzipori S, Widmer G. A hundred-year retrospective on cryptosporidiosis. Trends Parasitol 2008; 24:184–189.
8. Navin TR, Juranek DD. Cryptosporidiosis: clinical, epidemiologic, and parasitologic review. Rev Infect Dis 1984; 6:313–327.
9. Colford JM Jr, Tager IB, Hirozawa AM, Lemp GF, Aragon T, Petersen C. Cryptosporidiosis among patients infected with human immunodeficiency virus. Factors related to symptomatic infection and survival. Am J Epidemiol 1996; 144:807–816.
10. Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998; 351:256–261.
11. Foudraine NA, Weverling GJ, van Gool T, Roos MT, de Wolf F, Koopmans PP, et al
. Improvement of chronic diarrhoea in patients with advanced HIV-1 infection during potent antiretroviral therapy. AIDS 1998; 12:35–41.
12. Miao YM, Awad-El-Kariem FM, Franzen C, Ellis DS, Muller A, Counihan HM, et al
. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000; 25:124–129.
13. Maggi P, Larocca AM, Quarto M, Serio G, Brandonisio O, Angarano G, et al
. Effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 2000; 19:213–217.
14. Nannini EC, Okhuysen PC. HIV1 and the gut in the era of highly active antiretroviral therapy. Curr Gastroenterol Rep 2002; 4:392–398.
15. Werneck-Silva AL, Prado IB. Gastroduodenal opportunistic infections and dyspepsia in HIV-infected patients in the era of highly active antiretroviral therapy. J Gastroenterol Hepatol 2009; 24:135–139.
16. Call SA, Heudebert G, Saag M, Wilcox CM. The changing etiology of chronic diarrhea in HIV-infected patients with CD4 cell counts less than 200 cells/mm3
. Am J Gastroenterol 2000; 95:3142–3146.
17. Misra SN, Sengupta D, Satpathy SK. AIDS in India: recent trends in opportunistic infections. Southeast Asian J Trop Med Public Health 1998; 29:373–376.
18. Savioli L, Smith H, Thompson A. Giardia and Cryptosporidium join the ‘Neglected Diseases Initiative’
. Trends Parasitol
19. Hunter PR, Nichols G. Epidemiology and clinical features of Cryptosporidium
infection in immunocompromised patients. Clin Microbiol Rev 2002; 15:145–154.
20. Kuhls TL, Mosier DA, Crawford DL, Griffis J. Seroprevalence of cryptosporidial antibodies during infancy, childhood, and adolescence. Clin Infect Dis 1994; 18:731–735.
21. Leach CT, Koo FC, Kuhls TL, Hilsenbeck SG, Jenson HB. Prevalence of Cryptosporidium parvum infection in children along the Texas-Mexico border and associated risk factors. Am J Trop Med Hyg 2000; 62:656–661.
22. Frost FJ, Muller T, Craun GF, Lockwood WB, Calderon RL. Serological evidence of endemic waterborne cryptosporidium infections. Ann Epidemiol 2002; 12:222–227.
23. Lake IR, Nichols G, Bentham G, Harrison FC, Hunter PR, Kovats SR. Cryptosporidiosis decline after regulation, England and Wales, 1989–2005. Emerg Infect Dis 2007; 13:623–625.
24. Yoder JS, Harral C, Beach MJ. Cryptosporidiosis surveillance: United States, 2006–2008. MMWR Surveill Summ 2010; 59:1–14.
25. Kaushik K, Khurana S, Wanchu A, Malla N. Evaluation of staining techniques, antigen detection and nested PCR for the diagnosis of cryptosporidiosis in HIV seropositive and seronegative patients. Acta Trop 2008; 107:1–7.
26. Jayalakshmi J, Appalaraju B, Mahadevan K. Evaluation of an enzyme-linked immunoassay for the detection of Cryptosporidium antigen in fecal specimens of HIV/AIDS patients. Indian J Pathol Microbiol 2008; 51:137–138.
27. Navin TR, Weber R, Vugia DJ, Rimland D, Roberts JM, Addiss DG, et al
. Declining CD4+ T-lymphocyte counts are associated with increased risk of enteric parasitosis and chronic diarrhea: results of a 3-year longitudinal study. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20:154–159.
28. Flanigan T, Whalen C, Turner J, Soave R, Toerner J, Havlir D, et al
. Cryptosporidium infection and CD4 counts. Ann Intern Med 1992; 116:840–842.
29. Sorvillo F, Beall G, Turner PA, Beer VL, Kovacs AA, Kraus P, et al
. Seasonality and factors associated with cryptosporidiosis among individuals with HIV infection. Epidemiol Infect 1998; 121:197–204.
30. Khalakdina A, Tabnak F, Sun RK, Colford JM Jr. Race/ethnicity and other risk of factors associated with cryptosporidiosis as an initial AIDS-defining condition in California, 1980–99. Epidemiol Infect 2001; 127:535–543.
31. Caputo C, Forbes A, Frost F, Sinclair MI, Kunde TR, Hoy JF, et al
. Determinants of antibodies to Cryptosporidium
infection among gay and bisexual men with HIV infection. Epidemiol Infect 1999; 122:291–297.
32. Hellard M, Hocking J, Willis J, Dore G, Fairley C. Risk factors leading to Cryptosporidium infection in men who have sex with men. Sex Transm Infect 2003; 79:412–414.
33. Inungu JN, Morse AA, Gordon C. Risk factors, seasonality, and trends of cryptosporidiosis among patients infected with human immunodeficiency virus. Am J Trop Med Hyg 2000; 62:384–387.
34. Rose JB, Huffman DE, Gennaccaro A. Risk and control of waterborne cryptosporidiosis. FEMS Microbiol Rev 2002; 26:113–123.
35. Xiao L, Feng Y. Zoonotic cryptosporidiosis. FEMS Immunol Med Microbiol 2008; 52:309–323.
36. Preliminary FoodNet Data on the incidence of infection with pathogens transmitted commonly through food: 10 States, 2008. MMWR Morb Mortal Wkly Rep
37. Xiao L, Ryan UM. Cryptosporidiosis: an update in molecular epidemiology. Curr Opin Infect Dis 2004; 17:483–490.
38. Okhuysen PC, Chappell CL, Crabb JH, Sterling CR, DuPont HL. Virulence of three distinct Cryptosporidium parvum isolates for healthy adults. J Infect Dis 1999; 180:1275–1281.
39. Mac Kenzie WR, Hoxie NJ, Proctor ME, Gradus MS, Blair KA, Peterson DE, et al
. A massive outbreak in Milwaukee of cryptosporidium infection transmitted through the public water supply. N Engl J Med 1994; 331:161–167.
40. Hoxie NJ, Davis JP, Vergeront JM, Nashold RD, Blair KA. Cryptosporidiosis-associated mortality following a massive waterborne outbreak in Milwaukee, Wisconsin. Am J Public Health 1997; 87:2032–2035.
41. Rotz LD, Khan AS, Lillibridge SR, Ostroff SM, Hughes JM. Public health assessment of potential biological terrorism agents. Emerg Infect Dis 2002; 8:225–230.
42. 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 2007; 63:387–393.
43. Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy. Semin Liver Dis 2002; 22:277–289.
44. Mor SM, Tumwine JK, Ndeezi G, Srinivasan MG, Kaddu-Mulindwa DH, Tzipori S, et al. Respiratory cryptosporidiosis in HIV-seronegative children in Uganda: potential for respiratory transmission. Clin Infect Dis
45. Manabe YC, Clark DP, Moore RD, Lumadue JA, Dahlman HR, Belitsos PC, et al
. Cryptosporidiosis in patients with AIDS: correlates of disease and survival. Clin Infect Dis 1998; 27:536–542.
46. False-positive laboratory tests for Cryptosporidium involving an enzyme-linked immunosorbent assay: United States, November 1997–March 1998. MMWR Morb Mortal Wkly Rep
47. Ajjampur SSR, Rajendran P, Banerjee I, Ramani S, Monica B, Sankaran P, et al
. Closing the diagnostic gap in diarrhoea in Indian children by the application of molecular techniques. J Med Microbiol 2008; 57:1364–1368.
48. Morgan UM, Pallant L, Dwyer BW, Forbes DA, Rich G, Thompson RC. Comparison of PCR and microscopy for detection of Cryptosporidium parvum
in human fecal specimens: clinical trial. J Clin Microbiol 1998; 36:995–998.
49. Stockdale HD, Spencer JA, Blagburn BL. Prophylaxis and chemotherapy. In: Fayer R, Xiao L, editors. Cryptosporidium and cryptosporidiosis. Boca Raton: CRC Press; 2008. pp. 255–279.
50. Fox LM, Saravolatz LD. Nitazoxanide: a new thiazolide antiparasitic agent. Clin Infect Dis 2005; 40:1173–1180.
51. White AJ. Nitazoxanide: a new broad spectrum antiparasitic agent. Expert Rev Antiinfect Ther 2004; 2:43–49.
52. Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK. Prevention and treatment of cryptosporidiosis in immunocompromised patients
. Cochrane Database Syst Rev
53. Amadi B, Mwiya M, Sianongo S, Payne L, Watuka A, Katubulushi M, et al
. High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial. BMC Infect Dis 2009; 9:195.
54. Rossignol JF. Cryptosporidium
: treatment options and prospects for new drugs. Exp Parasitol 2010; 124:45–53.
55. Mele R, Gomez Morales MA, Tosini F, Pozio E. Indinavir reduces Cryptosporidium parvum
infection in both in vitro and in vivo models. Int J Parasitol 2003; 33:757–764.
56. Hommer V, Eichholz J, Petry F. Effect of antiretroviral protease inhibitors alone, and in combination with paromomycin, on the excystation, invasion and in vitro development of Cryptosporidium parvum. J Antimicrob Chemother 2003; 52:359–364.
57. Sun T, Teichberg S. Protozoal infections in the acquired immunodeficiency syndrome. J Electron Microsc Tech 1988; 8:79–103.
58. Xiao L. Molecular epidemiology of cryptosporidiosis: an update. Exp Parasitol 2010; 124:80–89.
59. Ajjampur SS, Gladstone BP, Selvapandian D, Muliyil JP, Ward H, Kang G. Molecular and spatial epidemiology of cryptosporidiosis in children in a semiurban community in South India. J Clin Microbiol 2007; 45:915–920.
60. Ajjampur SS, Sankaran P, Kang G. Cryptosporidium species in HIV-infected individuals in India: an overview. Natl Med J India 2008; 21:178–184.
61. Muthusamy D, Rao SS, Ramani S, Monica B, Banerjee I, Abraham OC, et al
. Multilocus genotyping of Cryptosporidium
sp. isolates from human immunodeficiency virus-infected individuals in South India. J Clin Microbiol 2006; 44:632–634.
62. Cama VA, Ross JM, Crawford S, Kawai V, Chavez-Valdez R, Vargas D, et al
. Differences in clinical manifestations among Cryptosporidium
species and subtypes in HIV-infected persons. J Infect Dis 2007; 196:684–691.
63. Rao Ajjampur SS, Asirvatham JR, Muthusamy D, Gladstone BP, Abraham OC, Mathai D, et al
. Clinical features & risk factors associated with cryptosporidiosis in HIV infected adults in India. Indian J Med Res 2007; 126:553–557.
64. Houpt ER, Bushen OY, Sam NE, Kohli A, Asgharpour A, Ng CT, et al
. Short report: asymptomatic Cryptosporidium hominis
infection among human immunodeficiency virus-infected patients in Tanzania. Am J Trop Med Hyg 2005; 73:520–522.
65. Theodos CM. Innate and cell-mediated immune responses to Cryptosporidium parvum
. Adv Parasitol 1998; 40:87–119.
66. Riggs MW. Recent advances in cryptosporidiosis: the immune response. Microbes Infect 2002; 4:1067–1080.
67. Borad A, Ward H. Human immune responses in cryptosporidiosis. Future Microbiol 2010; 5:507–519.
68. Leav BA, Yoshida M, Rogers K, Cohen S, Godiwala N, Blumberg RS, et al
. An early intestinal mucosal source of gamma interferon is associated with resistance to and control of Cryptosporidium parvum infection in mice. Infect Immun 2005; 73:8425–8428.
69. Hayward AR, Chmura K, Cosyns M. Interferon-gamma is required for innate immunity to Cryptosporidium parvum
in mice. J Infect Dis 2000; 182:1001–1004.
70. Takeuchi D, Jones VC, Kobayashi M, Suzuki F. Cooperative role of macrophages and neutrophils in host Antiprotozoan resistance in mice acutely infected with Cryptosporidium parvum
. Infect Immun 2008; 76:3657–3663.
71. Pollok RC, Farthing MJ, Bajaj-Elliott M, Sanderson IR, McDonald V. Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum
. Gastroenterology 2001; 120:99–107.
72. White AC, Robinson P, Okhuysen PC, Lewis DE, Shahab I, Lahoti S, et al
. Interferon-gamma expression in jejunal biopsies in experimental human cryptosporidiosis correlates with prior sensitization and control of oocyst excretion. J Infect Dis 2000; 181:701–709.
73. Choudhry N, Korbel DS, Edwards LA, Bajaj-Elliott M, McDonald V. Dysregulation of interferon-gamma-mediated signalling pathway in intestinal epithelial cells by Cryptosporidium parvum infection. Cell Microbiol
74. Robinson P, Okhuysen PC, Chappell CL, Lewis DE, Shahab I, Lahoti S, et al
. Expression of IL-15 and IL-4 in IFN-gamma-independent control of experimental human Cryptosporidium parvum
infection. Cytokine 2001; 15:39–46.
75. Chen XM, O'Hara SP, Nelson JB, Splinter PL, Small AJ, Tietz PS, et al
. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum
via activation of NF-kappaB. J Immunol 2005; 175:7447–7456.
76. Chen XM, Splinter PL, O'Hara SP, LaRusso NF. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum
infection. J Biol Chem 2007; 282:28929–28938.
77. Rogers KA, Rogers AB, Leav BA, Sanchez A, Vannier E, Uematsu S, et al
. MyD88-dependent pathways mediate resistance to Cryptosporidium parvum
infection in mice. Infect Immun 2006; 74:549–556.
78. Wanyiri J, Ward H. Association of mannose-binding lectin deficiency with cryptosporidiosis. Clin Infect Dis 2006; 43:295–296.
79. Kelly P, Jack DL, Naeem A, Mandanda B, Pollok RC, Klein NJ, et al
. Mannose-binding lectin is a component of innate mucosal defense against Cryptosporidium parvum
in AIDS. Gastroenterology 2000; 119:1236–1242.
80. Kirkpatrick BD, Huston CD, Wagner D, Noel F, Rouzier P, Pape JW, et al
. Serum mannose-binding lectin deficiency is associated with cryptosporidiosis in young Haitian children. Clin Infect Dis 2006; 43:289–294.
81. Carmolli M, Duggal P, Haque R, Lindow J, Mondal D, Petri WA Jr, et al
. Deficient serum mannose-binding lectin levels and MBL2 polymorphisms increase the risk of single and recurrent Cryptosporidium
infections in young children. J Infect Dis 2009; 200:1540–1547.
82. Petry F, Jakobi V, Wagner S, Tessema TS, Thiel S, Loos M. Binding and activation of human and mouse complement by Cryptosporidium parvum (Apicomplexa) and susceptibility of C1q- and MBL-deficient mice to infection. Mol Immunol 2008; 45:3392–3400.
83. Le Moing V, Bissuel F, Costagliola D, Eid Z, Chapuis F, Molina JM, et al
. Decreased prevalence of intestinal cryptosporidiosis in HIV-infected patients concomitant to the widespread use of protease inhibitors. AIDS 1998; 12:1395–1397.
84. Gomez Morales MA, Ausiello CM, Urbani F, Pozio E. Crude extract and recombinant protein of Cryptosporidium parvum
oocysts induce proliferation of human peripheral blood mononuclear cells in vitro. J Infect Dis 1995; 172:211–216.
85. Gomez Morales MA, La Rosa G, Ludovisi A, Onori AM, Pozio E. Cytokine profile induced by Cryptosporidium
antigen in peripheral blood mononuclear cells from immunocompetent and immunosuppressed persons with cryptosporidiosis. J Infect Dis 1999; 179:967–973.
86. Gomez Morales MA, Mele R, Ludovisi A, Bruschi F, Tosini F, Rigano R, et al
. Cryptosporidium parvum-specific CD4 Th1 cells from sensitized donors responding to both fractionated and recombinant antigenic proteins. Infect Immun 2004; 72:1306–1310.
87. Bonafonte MT, Smith LM, Mead JR. A 23-kDa recombinant antigen of Cryptosporidium parvum
induces a cellular immune response on in vitro stimulated spleen and mesenteric lymph node cells from infected mice. Exp Parasitol 2000; 96:32–41.
88. Ehigiator HN, Romagnoli P, Borgelt K, Fernandez M, McNair N, Secor WE, et al
. Mucosal cytokine and antigen-specific responses to Cryptosporidium parvum
in IL-12p40 KO mice. Parasite Immunol 2005; 27:17–28.
89. Singh I, Theodos C, Tzipori S. Recombinant proteins of Cryptosporidium parvum
induce proliferation of mesenteric lymph node cells in infected mice. Infect Immun 2005; 73:5245–5248.
90. Theodos CM, Sullivan KL, Griffiths JK, Tzipori S. Profiles of healing and nonhealing Cryptosporidium parvum
infection in C57BL/6 mice with functional B and T lymphocytes: the extent of gamma interferon modulation determines the outcome of infection. Infect Immun 1997; 65:4761–4769.
91. Guk SM, Yong TS, Chai JY. Role of murine intestinal intraepithelial lymphocytes and lamina propria lymphocytes against primary and challenge infections with Cryptosporidium parvum
. J Parasitol 2003; 89:270–275.
92. McDonald V, Bancroft GJ. Mechanisms of innate and acquired resistance to Cryptosporidium parvum
infection in SCID mice. Parasite Immunol 1994; 16:315–320.
93. Adjei AA, Jones JT, Enriquez FJ. Differential intra-epithelial lymphocyte phenotypes following Cryptosporidium parvum
challenge in susceptible and resistant athymic strains of mice. Parasitol Int 2000; 49:119–129.
94. Cosyns M, Tsirkin S, Jones M, Flavell R, Kikutani H, Hayward AR. Requirement of CD40-CD40 ligand interaction for elimination of Cryptosporidium parvum from mice. Infect Immun 1998; 66:603–607.
95. Hayward AR, Cosyns M, Jones M, Ponnuraj EM. Marrow-derived CD40-positive cells are required for mice to clear Cryptosporidium parvum
infection. Infect Immun 2001; 69:1630–1634.
96. Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al
. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003; 82:373–384.
97. Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al
. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997; 131:47–54.
98. You X, Mead JR. Characterization of experimental Cryptosporidium parvum
infection in IFN-gamma knockout mice. Parasitology 1998; 117(Pt 6):525–531.
99. Aguirre SA, Perryman LE, Davis WC, McGuire TC. IL-4 protects adult C57BL/6 mice from prolonged Cryptosporidium parvum infection: analysis of CD4+alpha beta+IFN-gamma+ and CD4+alpha beta+IL-4+ lymphocytes in gut-associated lymphoid tissue during resolution of infection. J Immunol 1998; 161:1891–1900.
100. McDonald SA, O'Grady JE, Bajaj-Elliott M, Notley CA, Alexander J, Brombacher F, et al
. Protection against the early acute phase of Cryptosporidium parvu
m infection conferred by interleukin-4-induced expression of T helper 1 cytokines. J Infect Dis 2004; 190:1019–1025.
101. Tessema TS, Dauber E, Petry F. Adoptive transfer of protective immunity from Cryptosporidium parvum
-infected interferon-gamma and interleukin-12-deficient mice to naive recipients. Vaccine 2009; 27:6575–6581.
102. Tessema TS, Schwamb B, Lochner M, Forster I, Jakobi V, Petry F. Dynamics of gut mucosal and systemic Th1/Th2 cytokine responses in interferon-gamma and interleukin-12p40 knock out mice during primary and challenge Cryptosporidium parvum
infection. Immunobiology 2009; 214:454–466.
103. Jakobi V, Petry F. Humoral immune response in IL-12 and IFN-gamma deficient mice after infection with Cryptosporidium parvum
. Parasite Immunol 2008; 30:151–161.
104. Ehigiator HN, McNair N, Mead JR. Cryptosporidium parvum: the contribution of Th1-inducing pathways to the resolution of infection in mice. Exp Parasitol 2007; 115:107–113.
105. Lean IS, McDonald SA, Bajaj-Elliott M, Pollok RC, Farthing MJ, McDonald V. Interleukin-4 and transforming growth factor beta have opposing regulatory effects on gamma interferon-mediated inhibition of Cryptosporidium parvum
reproduction. Infect Immun 2003; 71:4580–4585.
106. Chen W, Harp JA, Harmsen AG. Cryptosporidium parvum infection in gene-targeted B cell-deficient mice. J Parasitol 2003; 89:391–393.
107. Chappell CL, Okhuysen PC, Sterling CR, Wang C, Jakubowski W, Dupont HL. Infectivity of Cryptosporidium parvum
in healthy adults with preexisting anti-C. parvum
serum immunoglobulin G. Am J Trop Med Hyg 1999; 60:157–164.
108. Moss DM, Lammie PJ. Proliferative responsiveness of lymphocytes from Cryptosporidium parvum
-exposed mice to two separate antigen fractions from oocysts. Am J Trop Med Hyg 1993; 49:393–401.
109. Frost FJ, Roberts M, Kunde TR, Craun G, Tollestrup K, Harter L, et al
. How clean must our drinking water be: the importance of protective immunity. J Infect Dis 2005; 191:809–814.
110. Crabb JH. Antibody-based immunotherapy of cryptosporidiosis. Adv Parasitol 1998; 40:121–149.
111. Martin-Gomez S, Alvarez-Sanchez MA, Rojo-Vazquez FA. Oral administration of hyperimmune anti-Cryptosporidium parvum
ovine colostral whey confers a high level of protection against cryptosporidiosis in newborn NMRI mice. J Parasitol 2005; 91:674–678.
112. Sagodira S, Buzoni-Gatel D, Iochmann S, Naciri M, Bout D. Protection of kids against Cryptosporidium parvum
infection after immunization of dams with CP15-DNA. Vaccine 1999; 17:2346–2355.
113. Kobayashi C, Yokoyama H, Nguyen SV, Kodama Y, Kimata T, Izeki M. Effect of egg yolk antibody on experimental Cryptosporidium parvum
infection in scid mice. Vaccine 2004; 23:232–235.
114. Cama VA, Sterling CR. Hyperimmune hens as a novel source of anti-Cryptosporidium
antibodies suitable for passive immune transfer. J Protozool 1991; 38:42S–43S.
115. Greenberg PD, Cello JP. Treatment of severe diarrhea caused by Cryptosporidium parvum
with oral bovine immunoglobulin concentrate in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13:348–354.
116. Shield J, Melville C, Novelli V, Anderson G, Scheimberg I, Gibb D, et al
. Bovine colostrum immunoglobulin concentrate for cryptosporidiosis in AIDS. Arch Dis Child 1993; 69:451–453.
117. Nord J, Ma P, DiJohn D, Tzipori S, Tacket CO. Treatment with bovine hyperimmune colostrum of cryptosporidial diarrhea in AIDS patients. AIDS 1990; 4:581–584.
118. Okhuysen PC, Chappell CL, Crabb J, Valdez LM, Douglass ET, DuPont HL. Prophylactic effect of bovine anti-Cryptosporidium
hyperimmune colostrum immunoglobulin in healthy volunteers challenged with Cryptosporidium parvum
. Clin Infect Dis 1998; 26:1324–1329.
119. Perryman LE, Kapil SJ, Jones ML, Hunt EL. Protection of calves against cryptosporidiosis with immune bovine colostrum induced by a Cryptosporidium parvum
recombinant protein. Vaccine 1999; 17:2142–2149.
120. Riggs MW, Schaefer DA, Kapil SJ, Barley-Maloney L, Perryman LE. Efficacy of monoclonal antibodies against defined antigens for passive immunotherapy of chronic gastrointestinal cryptosporidiosis. Antimicrob Agents Chemother 2002; 46:275–282.
121. Haase AT. Perils at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol 2005; 5:783–792.
122. Schmidt W, Wahnschaffe U, Schafer M, Zippel T, Arvand M, Meyerhans A, et al
. Rapid increase of mucosal CD4 T cells followed by clearance of intestinal cryptosporidiosis in an AIDS patient receiving highly active antiretroviral therapy. Gastroenterology 2001; 120:984–987.
123. Kaushik K, Khurana S, Wanchu A, Malla N. Lymphoproliferative and cytokine responses to Cryptosporidium parvum
in patients coinfected with C. parvum
and human immunodeficiency virus. Clin Vaccine Immunol 2009; 16:116–121.
124. Wang HC, Dann SM, Okhuysen PC, Lewis DE, Chappell CL, Adler DG, et al
. High levels of CXCL10 are produced by intestinal epithelial cells in AIDS patients with active cryptosporidiosis but not after reconstitution of immunity. Infect Immun 2007; 75:481–487.
125. O'Hara SP, Small AJ, Nelson JB, Badley AD, Chen XM, Gores GJ, et al
. The human immunodeficiency virus type 1 Tat protein enhances Cryptosporidium parvum
-induced apoptosis in cholangiocytes via a Fas ligand-dependent mechanism. Infect Immun 2007; 75:684–696.
126. Yoder JS, Beach MJ. Cryptosporidium surveillance and risk factors in the United States. Exp Parasitol 2010; 124:31–39.
127. Valderrama AL, Hlavsa MC, Cronquist A, Cosgrove S, Johnston SP, Roberts JM, et al. Multiple risk factors associated with a large statewide increase in cryptosporidiosis
. Epidemiol Infect
128. Egorov A, Frost F, Muller T, Naumova E, Tereschenko A, Ford T. Serological evidence of Cryptosporidium
infections in a Russian city and evaluation of risk factors for infections. Ann Epidemiol 2004; 14:129–136.
129. Roy SL, DeLong SM, Stenzel SA, Shiferaw B, Roberts JM, Khalakdina A, et al
. Risk factors for sporadic cryptosporidiosis among immunocompetent persons in the United States from 1999 to 2001. J Clin Microbiol 2004; 42:2944–2951.
130. Boehmer TK, Alden NB, Ghosh TS, Vogt RL. Cryptosporidiosis from a community swimming pool: outbreak investigation and follow-up study
. Epidemiol Infect
131. Ethelberg S, Lisby M, Vestergaard LS, Enemark HL, Olsen KE, Stensvold CR, et al
. A foodborne outbreak of Cryptosporidium hominis infection. Epidemiol Infect 2009; 137:348–356.
132. Cruz JR, Cano F, Caceres P, Chew F, Pareja G. Infection and diarrhea caused by Cryptosporidium
sp. among Guatemalan infants. J Clin Microbiol 1988; 26:88–91.
133. Snel SJ, Baker MG, Venugopal K. The epidemiology of cryptosporidiosis in New Zealand, 1997–2006. N Z Med J 2009; 122:47–61.
134. Gait R, Soutar RH, Hanson M, Fraser C, Chalmers R. Outbreak of cryptosporidiosis among veterinary students. Vet Rec 2008; 162:843–845.
135. McGuigan CC, Steven K, Pollock KG. Cryptosporidiosis associated with wildlife center, Scotland. Emerg Infect Dis 2010; 16:895–896.
136. Cornet M, Romand S, Warszawski J, Bouree P. Factors associated with microsporidial and cryptosporidial diarrhea in HIV infected patients. Parasite 1996; 3:397–401.
137. Blanco MA, Iborra A, Vargas A, Nsie E, Mba L, Fuentes I. Molecular characterization of Cryptosporidium isolates from humans in Equatorial Guinea
. Trans R Soc Trop Med Hyg
138. Zavvar M, Sadraei J, Emadi H, Pirestani M. The use of a nested PCR-RFLP technique, based on the parasite's 18S ribosomal RNA, to characterise Cryptosporidium isolates from HIV/AIDS patients. Ann Trop Med Parasitol 2008; 102:597–601.
139. Nuchjangreed C, Boonrod K, Ongerth J, Karanis P. Prevalence and molecular characterization of human and bovine Cryptosporidium
isolates in Thailand. Parasitol Res 2008; 103:1347–1353.
140. Araujo AJ, Kanamura HY, Almeida ME, Gomes AH, Pinto TH, Da Silva AJ. Genotypic identification of Cryptosporidium
spp. isolated from HIV-infected patients and immunocompetent children of Sao Paulo, Brazil. Rev Inst Med Trop Sao Paulo 2008; 50:139–143.
141. Gatei W, Barrett D, Lindo JF, Eldemire-Shearer D, Cama V, Xiao L. Unique Cryptosporidium
population in HIV-infected persons, Jamaica. Emerg Infect Dis 2008; 14:841–843.
142. Samie A, Bessong PO, Obi CL, Sevilleja JE, Stroup S. Houpt E, et al. Cryptosporidium species: preliminary descriptions of the prevalence and genotype distribution among school children and hospital patients in the Venda region, Limpopo Province, South Africa
. Exp Parasitol
143. Llorente MT, Clavel A, Goni MP, Varea M, Seral C, Becerril R, et al
. Genetic characterization of Cryptosporidium
species from humans in Spain. Parasitol Int 2007; 56:201–205.
144. Raccurt CP, Brasseur P, Verdier RI, Li X, Eyma E, Stockman CP, et al
. Human cryptosporidiosis and Cryptosporidium
spp. in Haiti. Trop Med Int Health 2006; 11:929–934.
145. Tumwine JK, Kekitiinwa A, Bakeera-Kitaka S, Ndeezi G, Downing R, Feng X, et al
. Cryptosporidiosis and microsporidiosis in ugandan children with persistent diarrhea with and without concurrent infection with the human immunodeficiency virus. Am J Trop Med Hyg 2005; 73:921–925.
146. Cama VA, Bern C, Sulaiman IM, Gilman RH, Ticona E, Vivar A, et al
species and genotypes in HIV-positive patients in Lima, Peru. J Eukaryot Microbiol 2003; 50(Suppl):531–533.
147. Gatei W, Greensill J, Ashford RW, Cuevas LE, Parry CM, Cunliffe NA, et al
. Molecular analysis of the 18S rRNA gene of Cryptosporidium
parasites from patients with or without human immunodeficiency virus infections living in Kenya, Malawi, Brazil, the United Kingdom, and Vietnam. J Clin Microbiol 2003; 41:1458–1462.
148. Gatei W, Ashford RW, Beeching NJ, Kamwati SK, Greensill J, Hart CA. Cryptosporidium muris infection in an HIV-infected adult, Kenya. Emerg Infect Dis 2002; 8:204–206.
149. Leav BA, Mackay MR, Anyanwu A, RM OC, Cevallos AM, Kindra G, et al. Analysis of sequence diversity at the highly polymorphic Cpgp40/15 locus among Cryptosporidium isolates from human immunodeficiency virus-infected children in South Africa
. Infect Immun
150. Tiangtip R, Jongwutiwes S. Molecular analysis of Cryptosporidium
species isolated from HIV-infected patients in Thailand. Trop Med Int Health 2002; 7:357–364.
151. Morgan U, Weber R, Xiao L, Sulaiman I, Thompson RC, Ndiritu W, et al
. Molecular characterization of Cryptosporidium
isolates obtained from human immunodeficiency virus-infected individuals living in Switzerland, Kenya, and the United States. J Clin Microbiol 2000; 38:1180–1183.
152. Cevallos AM, Zhang X, Waldor MK, Jaison S, Zhou X, Tzipori S, et al
. Molecular cloning and expression of a gene encoding Cryptosporidium parvum
glycoproteins gp40 and gp15. Infect Immun 2000; 68:4108–4116.