Giardiasis treatment: an update with a focus on refractory disease

Postponed access: the file will be accessible after 2021.10.01Purpose of review Giardiasis remains a common cause of diarrhea and intestinal enteropathy globally. Here we give an overview of clinical treatment studies and discuss potential mechanisms and molecular targets for in-vitro testing of drug resistance. Recent findings Giardia is a cause of disease both in diarrheal and nondiarrheal cases. The prevalence of treatment refractory giardiasis is increasing. Recent studies reveal 5-nitroimidazole refractory infection occurs in up to 50% of cases. Mechanisms of drug resistance are not known. Placebo controlled studies of drug efficacy, taking the self-limiting course of giardiasis into account, has not been reported. No randomized controlled trials of treatment of refractory infection have been performed the last 25 years. Based on the clinical studies reported, combination treatment with a 5-nitroimidazole and a benzimidazole is more effective than repeated courses of 5-nitroimidazole or monotherapies in refractory cases. Quinacrine is effective in refractory cases, but potentially severe side effects limit its use. Summary A combination of a 5-nitroimidazole and albendazole or mebendazole, and quinacrine monotherapy, are rational choices in nitroimidazole refractory infections, but randomized controlled studies are needed. Further research into more recent clinical isolates is necessary to uncover mechanisms for the increase in metronidazole refractory giardiasis observed during the last decade.acceptedVersio

Human mucosal IgA immune responses against enterotoxigenic escherichia coli

Infection with enterotoxigenic Escherichia coli (ETEC) is a major contributor to diarrheal illness in children in low- and middle-income countries and travelers to these areas. There is an ongoing effort to develop vaccines against ETEC, and the most reliable immune correlate of protection against ETEC is considered to be the small intestinal secretory IgA response that targets ETEC-specific virulence factors. Since isolating IgA from small intestinal mucosa is technically and ethically challenging, requiring the use of invasive medical procedures, several other indirect methods are used as a proxy for gauging the small intestinal IgA responses. In this review, we summarize the literature reporting on anti-ETEC human IgA responses observed in blood, activated lymphocyte assayss, intestinal lavage/duodenal aspirates, and saliva from human volunteers being experimentally infected with ETEC. We describe the IgA response kinetics and responder ratios against classical and noncanonical ETEC antigens in the different sample types and discuss the implications that the results may have on vaccine development and testing.publishedVersio

Development of functional gastrointestinal disorders after Giardia lamblia infection

<p>Abstract</p> <p>Background</p> <p>Functional gastrointestinal disorders (FGID) may occur following acute gastroenteritis. This long-term complication has previously not been described after infection with the non-invasive protozoan <it>Giardia lamblia</it>. This study aims to characterize persistent abdominal symptoms elicited by <it>Giardia </it>infection according to Rome II criteria and symptoms scores.</p> <p>Methods</p> <p>Structured interview and questionnaires 12–30 months after the onset of <it>Giardia </it>infection, and at least 6 months after <it>Giardia </it>eradication, among 82 patients with persisting abdominal symptoms elicited by the <it>Giardia </it>infection. All had been evaluated to exclude other causes.</p> <p>Results</p> <p>We found that 66 (80.5%) of the 82 patients had symptoms consistent with irritable bowel syndrome (IBS) and 17 (24.3%) patients had functional dyspepsia (FD) according to Rome II criteria. IBS was sub classified into D-IBS (47.0%), A-IBS (45.5%) and C-IBS (7.6%). Bloating, diarrhoea and abdominal pain were reported to be most severe. Symptoms exacerbation related to specific foods were reported by 45 (57.7%) patients and to physical or mental stress by 34 (44.7%) patients.</p> <p>Conclusion</p> <p>In the presence of an IBS-subtype pattern consistent with post-infectious IBS (PI-IBS), and in the absence of any other plausible causes, we conclude that acute <it>Giardia </it>infection may elicit functional gastrointestinal diseases with food and stress related symptoms similar to FGID patients in general.</p

No difference in serum levels of B-cell activating receptor and antibodies against cytolethal distending toxin B and flagellin in post-infectious irritable bowel syndrome and chronic fatigue syndrome after Giardia infection

Background and Aim Functional gastrointestinal disorders (FGIDs) and chronic fatigue syndrome (CFS) frequently occur as comorbid conditions to each other. A shared etiology of these syndromes has been proposed because of their shared symptomatology and triggering by infections. Antibodies against the bacterial antigens cytolethal distending toxin B (CdtB) and flagellin have been proposed to be biomarkers of irritable bowel syndrome (IBS), especially diarrhea-predominant IBS (IBS-D). It is unknown if they may also be associated with comorbid conditions such as CFS. On the other hand, elevated level of B-cell activating factor (BAFF) has been associated with CFS and inflammatory bowel disease (IBD) and subjective food intolerance. Methods We evaluated serum levels of anti-flagellin and anti-CdtB using an in-house enzyme-linked immunosorbent assay (ELISA) and BAFF with a commercially available ELISA kit in a cohort of patients who developed fatigue syndromes and/or FGIDs after Giardia infection, by comparing them with healthy controls without these conditions. Results We did not find significant differences in circulating BAFF, anti-CdtB, or anti-flagellin antibody levels in these patient groups compared to healthy controls. Therefore, our results do not support a role for BAFF, anti-CdtB, or anti-flagellin antibodies as universal biomarkers for IBS or CFS. Conclusion BAFF, anti-CdtB, or anti-flagellin antibodies cannot be considered as universal biomarkers for IBS or CFS.publishedVersio

Transition to PCR diagnosis of cryptosporidiosis and giardiasis in the Norwegian healthcare system: could the increase in reported cases be due to higher sensitivity or a change in the testing algorithm?

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Strong Association between Diarrhea and Concentration of Enterotoxigenic Escherichia coli Strain TW10722 in Stools of Experimentally Infected Volunteers

Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of diarrheal illness in children and travelers in low- and middle-income countries. When volunteers are infected with ETEC strains, as part of experimental infection studies, some do not develop diarrhea. To improve our understanding of how these volunteers are protected, we investigated the association between stool ETEC DNA concentration, as determined by quantitative PCR, and the development and severity of disease in 21 volunteers who had been experimentally infected with ETEC strain TW10722. We found a strong association between maximum stool ETEC DNA concentration and the development of diarrhea: all of the 11 volunteers who did not develop diarrhea had <0.99% TW10722-specific DNA in their stools throughout the follow-up period of up to 9 days, while all of the 10 volunteers who did develop diarrhea had maximum DNA concentrations of ≥0.99%. Most likely, these maximum stool TW10722 DNA concentrations reflect the level of intestinal colonization and the risk of experiencing diarrhea, thereby, seems to be directly dependent on the level of colonization. Thus, the development and availability of vaccines and other prophylactic measures, even if they only partially reduce colonization, could be important in the effort to reduce the burden of ETEC diarrhea.publishedVersio

Characterization of Glycosylation-Specific Systemic and Mucosal IgA Antibody Responses to Escherichia coli Mucinase YghJ (SslE)

Efforts to develop broadly protective vaccines against pathogenic Escherichia coli are ongoing. A potential antigen candidate for vaccine development is the metalloprotease YghJ, or SslE. YghJ is a conserved mucinase that is immunogenic, heavily glycosylated, and produced by most pathogenic E. coli. To develop efficacious YghJ-based vaccines, there is a need to investigate to what extent potentially protective antibody responses target glycosylated epitopes in YghJ and to describe variations in the quality of YghJ glycosylation in the E. coli population. In this study we estimated the proportion of anti-YghJ IgA antibodies that targeted glycosylated epitopes in serum and intestinal lavage samples from 21 volunteers experimentally infected with wild-type enterotoxigenic E. coli (ETEC) strain TW10722. Glycosylated and non-glycosylated YghJ was expressed, purified, and then gycosylation pattern was verified by BEMAP analysis. Then we used a multiplex bead flow cytometric assay to analyse samples from before and 10 days after TW10722 was ingested. We found that 20 (95%) of the 21 volunteers had IgA antibody responses to homologous, glycosylated YghJ, with a median fold increase in IgA levels of 7.9 (interquartile range [IQR]: 7.1, 11.1) in serum and 3.7 (IQR: 2.1, 10.7) in lavage. The median proportion of anti-YghJ IgA response that specifically targeted glycosylated epitopes was 0.45 (IQR: 0.30, 0.59) in serum and 0.07 (IQR: 0.01, 0.22) in lavage. Our findings suggest that a substantial, but variable, proportion of the IgA antibody response to YghJ in serum during ETEC infection is targeted against glycosylated epitopes, but that gut IgA responses largely target non-glycosylated epitopes. Further research into IgA targeting glycosylated YghJ epitopes is of interest to the vaccine development efforts.publishedVersio

Clinical features of gastroenteritis during a large waterborne Campylobacter outbreak in Askøy, Norway

Purpose: Outbreaks of Campylobacter infection are common, but studies exploring the clinical features of acute illness in the outbreak setting are scarce in existing literature. The main purpose of the present study was to investigate the clinical features of self-reported acute illness in gastroenteritis cases during a large waterborne Campylobacter outbreak in Askøy municipality, Norway, in 2019. Methods: A web-based self-administered questionnaire, and invitation to participate was sent by the municipality of Askøy as text message to mobile phones using the municipality’s warning system to the inhabitants during the ongoing outbreak. Results. Out of 3624 participants, 749 (20.7%) were defined as cases, of which 177 (23.6%) reported severe gastroenteritis. The most common symptoms were loose stools (90.7%), abdominal pain (89.3%) and diarrhea (88.9%), whereas 63.8% reported fever, 50.2% joint pain and 14.2% bloody stools. Tiredness, a symptom non-specific to gastroenteritis, was the overall most common symptom (91.2%). Conclusion: About one in four of the cases reported symptoms consistent with severe gastroenteritis. We found more joint pain and less bloody stools than reported in published studies of laboratory confirmed campylobacteriosis cases. Tiredness was common in the current study, although rarely described in previous literature of acute illness in the outbreak setting.publishedVersio

Genetic diversity of circulating rotavirus strains in Tanzania prior to the introduction of vaccination

Background: Tanzania currently rolls out vaccination against rotavirus-diarrhea, a major cause of child illness and death. As the vaccine covers a limited number of rotavirus variants, this study describes the molecular epidemiology of rotavirus among children under two years in Dar es Salaam, Tanzania, prior to implementation of vaccination. Methods: Stool specimens, demographic and clinical information, were collected from 690 children admitted to hospital due to diarrhea (cases) and 545 children without diarrhea (controls) during one year. Controls were inpatient or children attending child health clinics. Rotavirus antigen was detected using ELISA and positive samples were typed by multiplex semi-nested PCR and sequencing. Results: The prevalence of rotavirus was higher in cases (32.5%) than in controls (7.7%, P,0.001). The most common G genotypes were G1 followed by G8, G12, and G4 in cases and G1, G12 and G8 in controls. The Tanzanian G1 variants displayed 94% similarity with the Rotarix vaccine G1 variant. The commonest P genotypes were P[8], P[4] and P[6], and the commonest G/P combination G1 P[8] (n = 123), G8 P[4] and G12 P[6]. Overall, rotavirus prevalence was higher in cool (23.9%) than hot months (17.1%) of the year (P = 0.012). We also observed significant seasonal variation of G genotypes. Rotavirus was most frequently found in the age group of four to six months. The prevalence of rotavirus in cases was lower in stunted children (28.9%) than in non-stunted children (40.1%, P = 0.003) and lower in HIV-infected (15.4%, 4/26) than in HIVuninfected children (55.3%, 42/76, P,0.001). Conclusion: This pre-vaccination study shows predominance of genotype G1 in Tanzania, which is phylogenetically distantly related to the vaccine strains. We confirm the emergence of genotype G8 and G12. Rotavirus infection and circulating genotypes showed seasonal variation. This study also suggests that rotavirus may not be an opportunistic pathogen in children infected with HIV

Symptomatic and asymptomatic secondary transmission of Cryptosporidium parvum following two related outbreaks in schoolchildren

Two related outbreaks (in 2009 and 2012) of cryptosporidiosis in Norwegian schoolchildren during a stay at a remote holiday farm provided us with a natural experiment to investigate possible secondary transmission of Cryptosporidium parvum IIa A19G1R1. After the children had returned home, clinical data and stool samples were obtained from their household contacts. Samples were investigated for the presence of Cryptosporidium oocysts by immunofluorescence antibody test. We found both asymptomatic and symptomatic infections, which are likely to have been secondary transmission. Laboratory-confirmed transmission rate was 17% [4/23, 95% confidence interval (CI) 7·0–37·1] in the 2009 outbreak, and 0% (95% CI 0–16·8) in the 2012 outbreak. Using a clinical definition, the probable secondary transmission rate in the 2012 outbreak was 8% (7/83, 95% CI 4·1–16·4). These findings highlight the importance of hygienic and public health measures during outbreaks or individual cases of cryptosporidiosis. We discuss our findings in light of previous studies reporting varying secondary transmission rates of Cryptosporidium spp