Paediatrician and Caregiver Awareness of Cryptosporidiosis and Giardiasis in Children: US Survey Responses.

There appears to be no published information concerning the awareness and knowledge about diarrhoea caused by Cryptosporidium spp. or Giardia lamblia among US paediatricians and caregivers of young children. Two concurrent, separate surveys were conducted among paediatricians and caregivers (~1000 respondents in each survey) of children ages 1-12 years concerning their knowledge, perceptions and attitudes in the diagnosis and treatment of parasitic diarrhoea. Awareness of parasite-induced diarrhoea was low for specific aspects among both paediatricians and caregivers. Educational efforts to improve awareness on the appropriate clinical presentation, management and treatment of cryptosporidiosis and giardiasis in children with persistent diarrhoea should be undertaken.

Host response and vaccine development to Helicobacter pylori infection.

Studies in both humans and animals demonstrate that H. pylori is capable of illiciting an innate response that in part is regulated by the genetic makeup of the host. These innate responses includes stimulating immune effector mechanisms at the cellular and biochemical level resulting in the influx of neutrophils into the lamina propria and have even been shown to modify gastric acid secretion. The availability of good animal models of chronic Helicobacter infection has also allowed investigators to begin to examine how the adaptive host immune response prevents and/or exacerbates Helicobacter-induced gastroduodenal disease. The experimental H. felis/mouse model has been utilized by a number of laboratories to investigate mechanisms of host defense against chronic Helicobacter infection. This model and the more recently developed H. pylori rodent model has not only allowed investigators to confirm the feasibility of immunotherapy to prevent and/or cure Helicobacter infection but also to begin to examine how the host immune response prevents and/or exacerbates Helicobacter-induced gastroduodenal disease. Based on these studies a hypothesis is emerging that suggests that protection and/or cure from Helicobacter infection is mediated primarily by an upregulated cellular immune response which may act via an antibody independent mechanism. Paradoxically, following natural infection with H. pylori, a component of the cellular immune response also promotes chronic gastric inflammation without clearance of the organism. The recent development of reliable and reproducible H. pylori/rodent models of disease and the availability of numerous inbred strains, transgenic and knockout animals, will allow investigators to continue to explore the role the host cellular and humoral immune response plays in promoting or preventing this infection.

Gastric LTi cells promote lymphoid follicle formation but are limited by IRAK-M and do not alter microbial growth.

Lymphoid tissue inducer (LTi) cells are activated by accessory cell IL-23, and promote lymphoid tissue genesis and antibacterial peptide production by the mucosal epithelium. We investigated the role of LTi cells in the gastric mucosa in the context of microbial infection. Mice deficient in IRAK-M, a negative regulator of TLR signaling, were investigated for increased LTi cell activity, and antibody mediated LTi cell depletion was used to analyze LTi cell dependent antimicrobial activity. H. pylori infected IRAK-M deficient mice developed increased gastric IL-17 and lymphoid follicles compared to wild type mice. LTi cells were present in naive and infected mice, with increased numbers in IRAK-M deficient mice by two weeks. Helicobacter and Candida infection of LTi cell depleted rag1(-/-) mice demonstrated LTi-dependent increases in calprotectin but not RegIII proteins. However, pathogen and commensal microbiota populations remained unchanged in the presence or absence of LTi cell function. These data demonstrate LTi cells are present in the stomach and promote lymphoid follicle formation in response to infection, but are limited by IRAK-M expression. Additionally, LTi cell mediated antimicrobial peptide production at the gastric epithelium is less efficacious at protecting against microbial pathogens than has been reported for other tissues.

Review article: Immunological determinants that may affect the Helicobacter pylori cancer risk.

A large body of literature supports a role for Helicobacter pylori as an environmental factor which contributes to the development of gastric cancer through an intermediate stage of atrophic gastritis. The mechanism(s) by which H. pylori-associated chronic inflammation progresses to more serious diseases such as peptic ulcer and gastric cancer in certain individuals is not clear. Variations in the phenotype or genotype of the infecting H. pylori strain can play a role in the severity of disease. However, individuals infected with the 'more virulent' strains of H. pylori often never develop serious disease. Our experiments in inbred strains of mice provide evidence that host genetics also play a significant role in H. pylori-related gastritis. We have demonstrated that gastritis is dominated by a TH1 adaptive immune response, the degree of which directly correlates with the severity of disease. Treatment of mice with IL-12 or anti-IFN-gamma antibodies can increase or decrease, respectively the severity of gastritis in infected mice and adoptive transfer of TH1 cell lines significantly exacerbates disease. Thus, the tendency of an individual to respond to infection with specific immune mechanisms can dramatically affect the severity of disease and possibly put an individual at increased risk of progressing to disorders such as gastric cancer.

Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial.

BACKGROUND: Gastro-oesophageal reflux afflicts up to 7% of all infants. Histamine-2 receptor antagonists are the most commonly prescribed medications for this disorder, but few controlled studies support this practice. AIM: To evaluate the safety and efficacy of famotidine for infant gastro-oesophageal reflux disease. METHODS: Thirty-five infants, 1.3-10.5 months of age, entered an 8-week, multi-centre, randomized, placebo-controlled, two-phase trial: first 4 weeks, observer-blind comparison of famotidine 0.5 mg/kg and famotidine 1.0 mg/kg; second 4 weeks, double-blind withdrawal comparison (safety and efficacy) of each dose with placebo. RESULTS: No serious adverse events were reported. Eleven patients had 16 non-serious, possibly drug-related adverse experiences: 6 patients with agitation or irritability (manifested as head-rubbing in two), 3 patients with somnolence, 2 patients with anorexia, 2 with headache, 1 patient with vomiting, 1 patient with hiccups, and 1 patient with candidiasis. Of the 35 infants, 27 completed Part I. There were significant score improvements for famotidine 0.5 mg/kg in regurgitation frequency (P = 0.04), and for famotidine 1.0 mg/kg in crying time (P = 0.027) and regurgitation frequency (P = 0.004) and volume (P = 0.01). Eight infants completed Part II on double-blind treatment, which was insufficient for meaningful comparisons. CONCLUSIONS: Histamine-2 receptor antagonists may cause agitation and headache in infants. A possibly efficacious famotidine dose for infants is 0.5 mg/kg (frequency adjusted for age). As 1.0 mg/kg may be more efficacious in some, the dosage may require individualization based on response. Further sizeable placebo-controlled evaluations of histamine-2 receptor antagonists in infants with gastro-oesophageal reflux disease are warranted.

Evaluation of QuickVue, a rapid enzyme immunoassay test for the detection of serum antibodies to Helicobacter pylori.

QuickVue is an enzyme immunoassay test for qualitative detection of serum immunoglobulin-G antibodies to Helicobacter pylori. We evaluated its ability to predict infection by H. pylori in 100 adult and 49 pediatric patients referred for gastric endoscopy. A patient was defined as infected with H. pylori if either culture or histology was positive. Of the 100 adult patients, 64 had H. pylori infection and QuickVue correctly identified 59 of the 64. Of 36 H. pylori-negative patients, 20 were correctly identified as negative by the test. In this sample of patients, QuickVue had a sensitivity of 92% and a specificity of 56%. In the 49 pediatric patients, QuickVue correctly identified nine of 11 infected cases and 34 of 38 noninfected patients. In this group, the sensitivity was 82% and the specificity was 89%. Overall the test had a sensitivity of 91% and a specificity of 73%. The positive predictive value was 77% and the negative predictive value was 89%.

Vaccine strategies for prevention of Helicobacter pylori infection.

OBJECTIVE: To examine the level and duration of the humoral immune response to Helicobacter felis following oral immunization or infection. DESIGN AND METHODS: Germ-free mice were orally immunized with sonicated H. felis plus cholera toxin five times over 6 weeks. One week after immunization was completed, immunized and control non-immunized mice received an oral challenge of live H. felis organisms. The animals were killed at 3-week intervals and serum, gastric washings, intestinal washings and gastric biopsies were obtained. H. felis infection was confirmed by a positive urease test or culture of the gastric biopsy. Serum gastric and intestinal antibody titers were determined by enzyme-linked immunosorbent assay. CONCLUSION: Infection and immunization against H. felis produces a specific humoral response. The humoral response in infection alone is significantly smaller than that of immunized animals until 6 weeks after infection. The humoral response following oral immunization persists for at least 18 weeks without further stimulation. The presence of an H. felis-specific antibody immune response before infection may be needed to protect animals from acute Helicobacter infection.

Local and systemic antibody responses in humans with Helicobacter pylori infection.

Immunization can prevent or cure an otherwise chronic helicobacter infection in several animal models despite the chronic nature of natural helicobacter infections. Differences in the antigenic specificity of the antibodies may contribute to the protection observed in these experimental animals. The goal of the present study was to compare the local and systemic antibody responses of humans with chronic Helicobacter pylori infection with those of an individual with spontaneous resolution of infection to find an immunological correlate of protection. Spontaneous resolution of infection was accompanied by a change in immunoblot profiles. Whereas a broad range of H pylori antigens was recognized in chronically infected patients (including the patient who ultimately cleared the infection spontaneously), resolution of infection in the absence of therapeutic agents resulted in the recognition of only several immunodominant antigens. The most dominant antigen was approximately 66 kDa in molecular mass. Immunoblot analysis demonstrated that these antibodies were specific for the structural subunits of the urease enzyme. These studies suggest that the success of antihelicobacter immunization may be due to the ability of vaccination to induce an immune response against antigens that are normally not immunodominant during the course of infection.

Relationship between gastric inflammatory response and symptoms in patients infected with Helicobacter pylori.

The relationship between the histologic severity of gastritis and associated symptoms was examined in 19 adult patients infected with Helicobacter pylori. At the time of gastrointestinal endoscopy, symptoms of dyspepsia were assessed by means of a linear analog scale. Gastric inflammation was quantitated with histomorphometric techniques. Symptoms such as epigastric pain, burping/belching, and nausea correlated with the degree of inflammation. These positive correlations suggest that the severity of the histologic gastritis contributes to the severity of symptoms. Therefore, utilization of a linear analog scale to assess symptoms may be a useful technique in evaluating the outcome of therapeutic trials of patients with symptomatic H. pylori infection.

What is the role for vaccination in Helicobacter pylori?

Helicobacter pylori has been implicated in the etiology of peptic ulcer disease, chronic gastritis, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Although significant progress has been made in treating this infection with combinations of either antimicrobial agents or antimicrobial agents plus proton pump inhibitors, these antimicrobial-based treatments continue to be suboptimal. Over the past few years it has become increasingly recognized that direct mucosal immunization can induce protection from infection at mucosal surfaces. Therefore, prevention of H. pylori infection by oral immunization is an alternative approach for the control of H. pylori disease. Using the Helicobacter felis mouse model or H. pylori mouse model, both prophylactic and therapeutic oral immunizations have been shown to be effective against H. pylori. In addition, several H. pylori proteins have been identified as potential candidate vaccines, and a phase 1 clinical trial has been completed that demonstrates the safety and tolerability of urease as a vaccine antigen. Such antigens in combination with a safe mucosal adjuvant could be used in the form of an oral vaccine administered during childhood before exposure to H. pylori to prevent infection. In addition, therapeutic immunization alone or as an adjunct to antimicrobial therapy may be capable of achieving a cure rate approaching 100%.

Oral immunization against Helicobacter pylori.

Helicobacter pylori, which has been associated with gastritis and duodenal ulcers, commonly chronically infects adults. Eradication of this microorganism, which is difficult to achieve, results in normalization of gastritis and marked reduction in the relapse rate of duodenal ulcers. Since eradication is difficult to achieve, prevention of initial colonization of the gastrointestinal tract may be a viable alternative for abrogation of H. pylori-associated gastroduodenal disease. To test the feasibility of this approach, mice and ferrets were orally immunized with killed H. pylori. Immunization induced immunoglobulin A and G anti-H. pylori antibodies in both gastrointestinal secretions and sera of mice. These responses were enhanced when cholera toxin was included in the immunization protocol as a mucosal adjuvant. In ferrets, addition of cholera toxin resulted in significant enhancement of anti-H. pylori antibody levels in sera and intestines. Thus, oral immunization with killed H. pylori may be feasible approach to protect hosts from this infection and the accompanying gastroduodenal disease.

Selective chemotaxis of subsets of B lymphocytes from gut-associated lymphoid tissue and its implications for the recruitment of mucosal plasma cells.

As they differentiate, precursor cells from the gut-associated lymphoid tissue are known to travel via the lymphatic system to the blood and then preferentially to home to various mucosal and exocrine sites such as the lamina propria of the gut and the lactating mammary gland, where they give rise to IgA-secreting plasma cells. The present study, directed at the mechanism by which the circulating precursors of mucosal IgA plasma cells selectively lodge in characteristic locations, explored the hypothesis that such homing is due to a locally produced chemotactic factor and that milk might be a source of such a factor. Subsets of lymphocytes bearing particular surface markers and purified by panning from lymph nodes of mice were examined in a micropore chemotaxis assay to search for the presence of chemotactic activity in mouse milk. The globulin fraction of whey was shown to contain a nondialyzable factor that is chemotactic for IgA (and also IgG)-positive lymphocytes when these are obtained from mesenteric lymph nodes as a source of mucosal-associated lymphoid tissue. Lymphocytes from peripheral lymph nodes, nonmucosal associated, were unaffected as were surface IgM-positive lymphocytes and T lymphocytes obtained from mesenteric nodes. Chemotactic activity for IgA lymphocytes was undetectable in mouse serum. The data are consistent with the idea that precursors of mucosal IgA plasma cells home to mucosal and exocrine sites in response to a specific chemotactic factor elaborated by local differentiated epithelial cells.

Opsonic activity of specific human IgG against Helicobacter pylori.

There is a strong association between chronic gastroduodenal disease in adults and children and the recovery of Helicobacter pylori (formerly Campylobacter pylori) from gastric biopsy specimens. However, data relevant to host defense mechanisms directed against this organism are scarce. The ability of H. pylori-specific antibody and complement to enhance the in vitro phagocytosis and killing of H. pylori by human peripheral blood polymorphonuclear leukocytes (PMNL) were studied. Sera with IgG antibody to H. pylori from five children with culture-proven H. pylori gastric disease markedly enhanced complement-dependent phagocytosis of H. pylori in an assay using flow cytometry to measure uptake of fluorescent-labeled bacteria by PMNL. Absorption of specific antibody from patient sera with an excess of H. pylori organisms completely abrogated this enhancement. IgG purified from plasma with high IgG antibody titers to H. pylori enhanced complement-dependent phagocytosis of H. pylori and increased the killing of this organism by PMNL in the presence of 5% human opsonic complement by one full log. IgG antibody to H. pylori appears to be highly functional in vitro in promoting complement-dependent phagocytosis and killing of H. pylori by PMNL.

Techniques for the evaluation of dyspepsia in children.

Dyspepsia can describe a subset of children with episodic or persistent abdominal symptoms--often related to feeding--that are thought to be caused by disorders of the proximal part of the digestive tract. Symptoms, such as vomiting, early satiety, postprandial epigastric abdominal pain, heartburn, abdominal fullness, poor weight gain, and/or anorexia, have been incorporated into the definition of dyspepsia. Unfortunately, presenting signs and symptoms in children with dyspepsia are nonspecific and can occur as a result of many diseases, such as parasitic infections, esophagitis, eosinophilic gastroenteritis, Helicobacter pylori infection, Crohn's disease, biliary tract or hepatic disease, pancreatitis, and lactose intolerance. This lack of specificity makes the evaluation of dyspepsia more difficult. Here, we describe an approach for the evaluation of dyspepsia that correlates in part with the child's presenting symptoms.

Campylobacter pylori: a new pathogen.

There is now considerable evidence suggesting that C. pylori is a human pathogen. The strong association between C. pylori and gastroduodenal disease is well documented. A number of hypotheses have been suggested for the pathogenic mechanisms of C. pylori-induced gastroduodenal disease, including the production of cytotoxins and the mechanical disruption of the epithelium. At the present time, treatment with a combination of antimicrobial agents eradicates the infection in approximately 50% of cases. Until an ideal therapeutic regimen is available, antimicrobial therapy is recommended only for those patients who continue to be symptomatic following 6 to 8 weeks of treatment with an H2-receptor.

Immunology of Helicobacter pylori and prospects for vaccine.

Since the initial discovery of H. pylori by Marshall and Warren 17 years ago, much progress has been made in treating this infection. However, as we enter the millennium, H. pylori infection continues to be one of the most common infections of mankind. In addition, eradication of H. pylori still requires multiple antimicrobial agents. A better understanding of the host immune response to H. pylori infection should allow investigators to develop immunotherapies to prevent the acquisition of infection and eradicate existing chronic H. pylori infection.