Indole metabolites generated by microbiota inhibit Cryptosporidium growth.

Funkhouser-Jones et al. recently identified gut metabolites that affected Cryptosporidium growth. A key focus, indole, was shown to inhibit the parasite in vivo and in vitro by decreasing the host mitochondria function and the membrane potential of parasite mitosomes. These findings help clarify the role microflora and metabolites play in host resistance.

Widespread occurrence of Cryptosporidium infections in patients with HIV/AIDS: Epidemiology, clinical feature, diagnosis, and therapy.

Cryptosporidium infection is a serious threat for HIV/AIDS patients, causing severe diarrhea and even death. The overall prevalence of Cryptosporidium in HIV/AIDS patients was calculated as approximately 8.69% (7,799/89,724), with higher prevalence observed in individuals with diarrhea, individuals with low CD4+ T-lymphocyte counts, and antiretroviral therapy-naïve individuals. Cryptosporidium infection was not significantly associated with patient age or gender, national development levels, or continent of residence. Over the period from 2007 to 2017, Cryptosporidium prevalence was 10.09% (3,282/32,517); this figure was higher than that observed in each of the previous observation periods (1985-1995 and 1996-2006), suggesting that the prevalence of cryptosporidiosis has been increasing over time in HIV/AIDS patients. Ten Cryptosporidium species and genotypes have been identified from 1,252 isolates, with C. hominis, C. parvum, and C. meleagridis accounting for 93.53% of infections. Five subtypes each of C. hominis (Ia, Ib, Id, Ie, and If), C. parvum (IIa to IIe), and C. meleagridis (IIIa to IIIe) have been described by sequence analyses of the 60-kDa glycoprotein (gp60) gene. Variation in the clinical manifestations observed in HIV/AIDS patients might be attributed to infection by different Cryptosporidium species, genotypes and subtypes, as well as different sites of infection. New molecular and immunological diagnostic techniques are in development or already commercially available. High-throughput screening methods for development of new or repurposed therapeutics as well as novel parasite genetic manipulation strategies offer hope for improving human cryptosporidiosis therapies. Painstaking efforts by researchers as well as support from governments and funding agencies will be required to make lasting achievements in this field.

Cryptosporidium and Giardia Infections in Children: A Review.

Diarrheal disease remains the second leading cause of mortality in children in developing countries. Cryptosporidium is a leading cause and its importance stands to increase as rotavirus vaccine becomes used around the world. Cryptosporidium is particularly problematic in children younger than 2 years old and in the immunocompromised. Giardia lamblia is a common intestinal protozoan that is associated with diarrhea and, perhaps, growth faltering in impoverished settings. This review establishes the current prevalence of these infections in global settings and reviews current diagnosis and management approaches.

Prevalence of Cryptosporidium Carriage and Disease in Children With Primary Immune Deficiencies Undergoing Hematopoietic Stem Cell Transplant in Northern Europe.

A prospective cohort study of children with primary immunodeficiencies undergoing hematopoietic stem cell transplant in the United Kingdom investigated the extent and significance of Cryptosporidium carriage in this high risk group. Three of 42 children recruited were infected with Cryptosporidium, a lower proportion than previously described. One had serious disease. The underlying immunodeficiency likely had a bearing on the clinical presentation and possible outcome of infection.

Human cryptosporidiosis in Europe.

Cryptosporidium has emerged as a significant cause of diarrhoeal disease worldwide, with severe health consequences for very young, malnourished children living in endemic areas and for individuals with highly impaired T-cell functions. In Europe, as elsewhere, the burden of disease has been difficult to measure as a result of the lack of appropriate, standardized surveillance and monitoring systems. The recent occurrence of large water- and foodborne outbreaks in several EU countries, as well as the results of many surveys of human and animal cryptosporidiosis, indicate that this parasite is widespread. Specific subtypes of the zoonotic Cryptosporidium parvum and the anthroponotic C. hominis are responsible for the majority of human cases in Europe. No treatment is currently available to clear the infection, but recent progress in genetic engineering of the parasite, coupled with advances in genomics, have opened important avenues for future research. Here we explore the possible reasons for underascertainment of cryptosporidiosis and the importance of accurate diagnosis in clinical management, the epidemiology of human cryptosporidiosis and key messages from recent outbreaks to highlight important interventions and emerging public health issues.

The evolution of respiratory Cryptosporidiosis: evidence for transmission by inhalation.

The protozoan parasite Cryptosporidium infects all major vertebrate groups and causes significant diarrhea in humans, with a spectrum of diseases ranging from asymptomatic to life-threatening. Children and immunodeficient individuals are disproportionately affected, especially in developing countries, where cryptosporidiosis contributes substantially to morbidity and mortality in preschool-age children. Despite the enormous disease burden from cryptosporidiosis, no antiprotozoal agent or vaccine exists for effective treatment or prevention. Cryptosporidiosis involving the respiratory tract has been described for avian species and mammals, including immunocompromised humans. Recent evidence indicates that respiratory cryptosporidiosis may occur commonly in immunocompetent children with cryptosporidial diarrhea and unexplained cough. Findings from animal models, human case reports, and a few epidemiological studies suggest that Cryptosporidium may be transmitted via respiratory secretions, in addition to the more recognized fecal-oral route. It is postulated that transmission of Cryptosporidium oocysts may occur by inhalation of aerosolized droplets or by contact with fomites contaminated by coughing. Delineating the role of the respiratory tract in disease transmission may provide necessary evidence to establish further guidelines for prevention of cryptosporidiosis.

Management of acute infectious diarrhea for children living in resource-limited settings.

Acute infectious gastroenteritis continues to be a leading cause of morbidity and mortality in children below 5 years of age, with the majority of deaths concentrated in 35 'low income' countries. In these countries the under five years of age mortality rates reach 100 per 1000 live births, of which a significant proportion are associated with acute diarrhea. Rotavirus, cryptosporidium, Shigella spp and enterotoxigenic Escherichia coli are the main pathogens causing disease in these settings, although other bacteria and parasites can cause moderate to severe disease in different regions and situations. Treatment of children in these setting should be focused on appropriate rehydration, early hospitalization of severely malnourished children, zinc supplementation, and in specific situations, antimicrobials should be considered. The rationale for antimicrobial use should be based on the potential benefits based on published literature and the opportunity for use. This review provides a pathogen-specific update on the potential benefits of antimicrobials and suggests an empirical management approach for children suffering an acute watery or bloody diarrhea in a resource-limited region.

Prospects for immunotherapy and vaccines against Cryptosporidium.

Cryptosporidium spp is a ubiquitous parasite that has long been recognized as a frequent cause of protozoal diarrhea in humans. While infections in immunocompetent hosts are usually self-limiting, immunocompromised individuals can develop severe, chronic, and life-threatening illness. Vaccine development or immunotherapy that prevents disease or reduces the severity of infection is a relevant option since efficacious drug treatments are lacking. In particular, children in developing countries might benefit the most from a vaccine since cryptosporidiosis in early childhood has been reported to be associated with subsequent impairment in growth, physical fitness, and intellectual capacity. In this review, immunotherapies that have been used clinically are described as well as experimental vaccines and their evaluation in vivo.

Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Probiotics have a possible role in the treatment of pediatric acute gastroenteritis. We report the effect of the probiotic Lactobacillus rhamnosus GG (LGG) on intestinal function, immune response, and clinical outcomes in Indian children with cryptosporidial or rotavirus diarrhea. METHODS: Children with gastroenteritis aged 6 months to 5 years, testing positive for either rotavirus or Cryptosporidium species in stool (coinfections were excluded), were randomized to LGG (ATCC 53103) or placebo, once daily for 4 weeks. Baseline demographic and clinical details were obtained. Sera were tested for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies to Cryptosporidium and rotavirus, and the lactulose to mannitol ratio for intestinal permeability was determined at baseline and at the end of follow-up. RESULTS: Of the 124 children enrolled, 82 and 42 had rotavirus and cryptosporidial diarrhea, respectively. Median diarrheal duration was 4 days; one-third of the children had severe diarrhea. Baseline and clinical parameters were comparable between children receiving LGG and placebo. At the end of follow-up, fewer children with rotavirus diarrhea on LGG had repeated diarrheal episodes (25% vs 46%; P = .048) and impaired intestinal function (48% vs 72%; P = .027). Significant increase in IgG levels postintervention (456 vs 2215 EU; P = .003) was observed in children with rotavirus diarrhea receiving LGG. Among children with cryptosporidial diarrhea, those receiving LGG showed significant improvement in intestinal permeability. CONCLUSIONS: LGG has a positive immunomodulatory effect and may be useful in decreasing repeated episodes of rotavirus diarrhea. Improvement in intestinal function in children with rotavirus and cryptosporidial gastroenteritis emphasizes the role of probiotics in treating intestinal impairment after infection. CLINICAL TRIALS REGISTRATION: CTRI/2010/091/000339.

Hyperimmune bovine colostrum for treatment of GI infections: a review and update on Clostridium difficile.

Hyperimmune bovine colostrum (HBC), produced by vaccination of a cow during gestation, is rich in targeted immunoglobulins, and can be used to treat a variety of diseases. The published history of HBC use for treating gastrointestinal infections in humans has developed over the past several decades and demonstrates the promise of this type of therapeutic for GI infectious disease. HBC, or purified derivative products, have been used successfully for treatment or prevention of cryptosporidiosis, shigellosis, rotavirus, enterotoxigenic E. coli, and C. difficile infection (CDI). Given the positive results of previous studies using HBC for treatment of CDI, we have produced HBC with antibodies against the two most important virulence factors of C. difficile, TcdA and TcdB, using a novel recombinant vaccine. Our preliminary results demonstrate efficacy of the HBC product for treatment of CDI in the gnotobiotic piglet model, and warrant more thorough investigation. HBC may provide an effective treatment alternative to antibiotics, which can spare the normal gut microflora, and reduce rates of recurrence and antibiotic resistance.

Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: case report and review of the literature.

A 43-year-old man with a hyper-immunoglobulin M syndrome due to CD40 ligand deficiency presented with insidious onset of recurrent diarrhoea and deranged liver function tests. Standard stool microscopy was repeatedly negative for cryptosporidia but immunofluorescent testing and polymerase chain reaction demonstrated the presence of infection eventually. Despite both paromomycin and nitazoxanide, he developed sclerosing cholangitis secondary to cryptosporidial infection. Whilst being considered for dual bone marrow and liver transplantation, he was found to have cholangiocarcinoma on imaging after three biopsies of a suspicious lesion. This is a rare complication of this combined immune deficiency predominantly in children that has not been reported previously in a long-term survivor with this condition.

Novel in vitro and in vivo models and potential new therapeutics to break the vicious cycle of Cryptosporidium infection and malnutrition.

BACKGROUND: Although several animal models of cryptosporidiosis have been reported, most involve genetically or pharmacologically immune-suppressed hosts. METHODS: We report challenge with excysted (in vitro and in vivo) and unexcysted (in vivo) Cryptosporidium parvum oocysts in human colonic adenocarcinoma (HCT-8) cells and weaned nourished and malnourished C57BL/6 mice, following outcomes of growth rate, stool shedding, and tissue burden. We tested treatment with an oligodeoxynucleotide containing unmethylated CpG motif (CpG-ODN) and alanyl-glutamine in vivo and in vitro. RESULTS: C. parvum-challenged mice showed prolonged weight loss (>10% over 4 days), robust stool shedding (>3 logs/d over 7 days), and epithelial infection in the ileum, cecum, and colon. Of 2 potential therapeutic compounds evaluated in the model, CpG-ODN reduced body weight loss (to <6% on days 3-7 after challenge), reduced shedding of organisms (by 25% on days 1 and 3 after challenge), and decreased the burden of parasites in the ileum. Alanyl-glutamine showed similar benefits. In vitro findings suggested that effects on the epithelial component of the mucosa probably likely responsible for beneficial effects seen in vivo. CONCLUSIONS: Weaned mice provide a convenient and reproducible model of cryptosporidial disease, including its vicious cycle with body weight loss and heavier infection with malnutrition, and this model may be useful in exploring innovative therapeutic solutions for this challenging infectious disease.

Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: a prospective single centre study.

Digestive cryptosporidiosis (DC) can mimic GVHD after allogeneic haematopoietic stem cell transplantation (HSCT), thus requiring a reduction of immunosuppressive drugs and a specific therapy, whereas GVHD requires an intensification of immunosuppression. We systematically searched for cryptosporidiosis by light microscopy, immunochromatography and PCR in HSCT recipients who presented with at least one episode of diarrhoea. Of 115 consecutive patients allografted between July 2006 and November 2008, we analysed stools in 52 of 56 patients meeting these criteria. We identified Cryptosporidium parvum in 5 of the 52 patients (9.6%) at a median of 503 days (range 20-790) after HSCT. In those five patients, the median CD4+ cell and B lymphocyte counts were 60/mm3 (0-234) and 0/mm3 (0-96), respectively. Two patients died of invasive fungal infections. In the other three patients, diarrhoea disappeared after a median of 5 weeks following onset of bitherapy with azithromycine and nitazoxanide; they were still alive 433, 380 and 1179 days after the DC diagnosis. DC is probably under diagnosed after HSCT because it is difficult to detect during the asymptomatic phase. Early bitherapy and reduction of immunosuppression seem efficacious. In our series, DC has a seasonal pattern and is promoted by profound T lymphopenia.

Cryptosporidium hominis and Isospora belli diarrhea in travelers returning from West Africa.

Travel-related diarrhea is common among tourists to developing countries. We report two cases of diarrhea due to Cryptosporidium hominis and Isospora belli, respectively, in a child and an adult returning from Africa, without other associated microorganisms. We emphasize the need to detect underdiagnosed coccidiosis in diarrheic travelers with specific methods.

Human immune responses in cryptosporidiosis.

Immune responses play a critical role in protection from, and resolution of, cryptosporidiosis. However, the nature of these responses, particularly in humans, is not completely understood. Both innate and adaptive immune responses are important. Innate immune responses may be mediated by Toll-like receptor pathways, antimicrobial peptides, prostaglandins, mannose-binding lectin, cytokines and chemokines. Cell-mediated responses, particularly those involving CD4(+) T cells and IFN-gamma play a dominant role. Mucosal antibody responses may also be involved. Proteins mediating attachment and invasion may serve as putative protective antigens. Further knowledge of human immune responses in cryptosporidiosis is essential in order to develop targeted prophylactic and therapeutic interventions. This review focuses on recent advances and future prospects in the understanding of human immune responses to Cryptosporidium infection.

Minireview: clinical cryptosporidiosis.

Cryptosporidium has emerged as an important cause of diarrhoeal illness worldwide, especially amongst young children and patients with immune deficiencies. Usually presenting as a gastro-enteritis-like syndrome, disease ranges in seriousness from mild to severe and signs and symptoms depend on the site of infection, nutritional and immune status of the host, and parasite-related factors. Sources and routes of transmission are multiple, involving both zoonotic and anthroponotic spread, and facilitated by the resistance of the parasite to many commonly used disinfectants. Prevention and control measures are important for the protection of vulnerable groups since treatment options are limited. This review covers the life cycle, pathogenesis, clinical presentations, diagnosis, prevention and management of cryptosporidiosis in humans.