Helminth infection induces a distinct subset of CD101hi lung tissue-infiltrating eosinophils that are differentially regulated by type 2 cytokines.

Eosinophils play divergent roles in health and disease, contributing to both immunoregulatory and proinflammatory responses. Helminth infection is strongly associated with eosinophilia and the induction of the type 2 cytokines interleukin (IL)-5, IL-4 and IL-13. This study aimed to elucidate the heterogeneity of pulmonary eosinophils in response to helminth infection and the roles of IL-5, IL-4 and IL-13 in driving pulmonary eosinophil responses. Using the murine helminth model Nippostrongylus brasiliensis (Nb), we characterize a subtype of eosinophils, defined by high expression of CD101, that is induced in the lungs of Nb-infected mice and are phenotypically distinct from lung eosinophils that express low levels of CD101. Strikingly, we show that the two eosinophil subtypes have distinct anatomical localization within the lung: CD101low eosinophils are predominantly localized in the lung vasculature, whereas Nb-induced CD101hi eosinophils are predominantly localized in the extravascular lung niche. We show that CD101hi eosinophils are also induced across other models of pulmonary infection and inflammation, including a nonlung-migrating helminth infection, house dust mite-induced allergic inflammation and influenza infection. Furthermore, we demonstrate that the induction of CD101hi tissue eosinophils is independent of IL-5 and IL-4 signaling, but is dependent on intact IL-13 signaling. These results suggest that IL-13 produced during helminth infection and other disease states promotes a pulmonary tissue-infiltrating program in eosinophils defined by high expression of CD101.

Modulation of intestinal epithelial permeability by chronic small intestinal helminth infections.

Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease.

The Disease Severity Index for Inflammatory Bowel Disease Is a Valid Instrument that Predicts Complicated Disease.

BACKGROUND: The disease severity index (DSI) for inflammatory bowel disease (IBD) combines measures of disease phenotype, inflammatory activity, and patient-reported outcomes. We aimed to validate the DSI and assess its utility in predicting a complicated IBD course. METHODS: A multicenter cohort of adults with IBD was recruited. Intraclass correlation coefficients (ICCs) and weighted Kappa assessed inter-rater reliability. Cronbach's alpha measured internal consistency of DSI items. Spearman's rank correlations compared the DSI with endoscopic indices, symptom indices, quality of life, and disability. A subgroup was followed for 24 months to assess for a complicated IBD course. Area under the receiver operating characteristics curve (AUROC) and multivariable logistic regression assessed the utility of the DSI in predicting disease progression. RESULTS: Three hundred and sixty-nine participants were included (Crohn's disease [CD], n = 230; female, n = 194; mean age, 46 years [SD, 15]; median disease duration, 11 years [interquartile range, 5-21]), of which 171 (CD, n = 99; ulcerative colitis [UC], n = 72) were followed prospectively. The DSI showed inter-rater reliability for CD (ICC 0.93, n = 65) and UC (ICC 0.97, n = 33). The DSI items demonstrated inter-rater agreement (Kappa > 0.4) and internal consistency (CD, α > 0.59; UC, α > 0.75). The DSI was significantly associated with endoscopic activity (CDn=141, r = 0.65, P < .001; UCn=105, r = 0.80, P < .001), symptoms (CDn=159, r = 0.69, P < .001; UCn=132, r = 0.58, P < .001), quality of life (CDn=198, r = -0.59, P < .001; UCn=128, r = -0.68, P < .001), and disability (CDn=83, r = -0.67, P < .001; UCn=52, r = -0.74, P < .001). A DSI of 23 best predicted a complicated IBD course (AUROC = 0.82, P < .001) and was associated with this end point on multivariable analyses (aOR, 9.20; 95% confidence interval, 3.32-25.49). CONCLUSIONS: The DSI reliably encapsulates factors contributing to disease severity and accurately prognosticates the longitudinal IBD course.

This study shows that the disease severity index (DSI) for inflammatory bowel disease (IBD) is a valid and reliable instrument encapsulating the disease phenotype, disease activity, and impact of the disease on the patient; and it accurately predicts for incident disease complications.

Helminths' therapeutic potential to treat intestinal barrier dysfunction.

The intestinal barrier is a dynamic multi-layered structure which can adapt to environmental changes within the intestinal lumen. It has the complex task of allowing nutrient absorption while limiting entry of harmful microbes and microbial antigens present in the intestinal lumen. Excessive entry of microbial antigens via microbial translocation due to 'intestinal barrier dysfunction' is hypothesised to contribute to the increasing incidence of allergic, autoimmune and metabolic diseases, a concept referred to as the 'epithelial barrier theory'. Helminths reside in the intestinal tract are in intimate contact with the mucosal surfaces and induce a range of local immunological changes which affect the layers of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory. This review will focus on the effect of helminths on intestinal barrier function and explore whether this could explain the proposed health benefits delivered by helminths.

Controlled Hookworm Infection for Medication-free Maintenance in Patients with Ulcerative Colitis: A Pilot, Double-blind, Randomized Control Trial.

BACKGROUND: Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC. METHODS: Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection. RESULTS: At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang's blinding index 0.22; 95% CI, -0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35 × 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL. CONCLUSIONS: A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible.

This pilot study has shown a full-scale RCT examining hookworm therapy as maintenance therapy in patients with ulcerative colitis is feasible, safe, and will be well-tolerated.

The Impact of Disease Activity on Sexual and Erectile Dysfunction in Patients With Inflammatory Bowel Disease.

BACKGROUND: Increased disease activity may be a risk factor for sexual dysfunction (SD) in patients with inflammatory bowel disease (IBD). This study investigated associations between objective measures of disease activity and sexual function. METHODS: Adults with IBD undergoing ileocolonoscopy were prospectively recruited. Demographic, sexual function (Female Sexual Function Index and International Index of Erectile Function), disease activity (endoscopic, biomarker, and symptoms), psychological symptoms, and quality-of-life data were collected. Rates of SD and erectile dysfunction (ED) were compared between patients with active and inactive inflammation and symptoms using the Fisher's exact test. Logistic regression examined associations between SD and ED, and disease characteristics and psychological symptoms. RESULTS: A total of 159 participants were included, 97 had Crohn's disease and 85 were women. SD was reported in 36 of 59 and 13 of 59 sexually active women and men, respectively and ED in 22 of 59 sexually active men. Rates of SD and ED were similar between individuals with active and inactive IBD based on endoscopic indices (P > .05) and biomarkers (P > .05). Women with active IBD symptoms experienced significantly higher rates of SD (P < .05), but men did not (P > .05). Multivariable logistic regression identified that symptoms of severe depression (odds ratio, 5.77; 95% confidence interval, 1.59-20.94) were associated with SD in women, and severe anxiety (odds ratio, 15.62; 95% confidence interval, 1.74-140.23) was associated with ED in men. CONCLUSIONS: Objective measures of disease activity are not associated with SD or ED in patients with IBD. Clinicians should consider concomitant psychological symptoms contributing to the sexual health of patients with IBD.

Faecal Myeloperoxidase as a Biomarker of Endoscopic Activity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD], consisting of Crohn's disease [CD] and ulcerative colitis [UC], is a relapsing-remitting illness. Treat-to-target IBD management strategies require monitoring of gastrointestinal inflammation. This study aimed to investigate faecal myeloperoxidase [fMPO], a neutrophil granule enzyme, as a biomarker of IBD activity. METHODS: Prospectively recruited participants with IBD, undergoing ileocolonoscopy for disease assessment, provided biological samples and completed symptom questionnaires prior to endoscopy. fMPO, C-reactive protein [CRP], and faecal calprotectin [fCal] were compared with validated endoscopic indices [simple endoscopic score for CD and UC endoscopic index of severity]. Receiver operating characteristic [ROC] curves assessed the performance of fMPO, CRP, and fCal in predicting endoscopic disease activity. Baseline biomarkers were used to predict a composite endpoint of complicated disease at 12 months [need for escalation of biologic/immunomodulator due to relapse, steroid use, IBD-related hospitalisation, and surgery]. RESULTS: A total of 172 participants were recruited [91 female, 100 with CD]. fMPO was significantly correlated with endoscopic activity in both CD [r = 0.53, p < 0.01] and UC [r = 0.63, p < 0.01], and with fCal in all patients with IBD [r = 0.82, p < 0.01]. fMPO was effective in predicting moderate-to-severely active CD [AUROC 0.86, p < 0.01] and UC [AUROC 0.92, p < 0.01]. Individuals with a baseline fMPO > 26 µg/g were significantly more likely to reach the composite outcome at 12 months (hazard ratio [HR] 3.71, 95% confidence interval [CI] 2.07-6.64, p < 0.01). CONCLUSIONS: Faecal myeloperoxidase is an accurate biomarker of endoscopic activity in IBD and predicted a more complicated IBD course during follow-up.

The disease severity index for inflammatory bowel disease is associated with psychological symptoms and quality of life, and predicts a more complicated disease course.

BACKGROUND: The Disease Severity Index (DSI) is a novel tool to predict disease severity in inflammatory bowel disease (IBD). However, its ability to predict disease complications and the presence of psychosocial comorbidity is unclear. AIMS: To assess prospectively associations between the DSI and psychological symptoms, quality-of-life (QoL) and disease outcomes in an IBD cohort. METHODS: Patients with IBD undergoing ileocolonoscopy were followed prospectively for 12 months. DSI, psychological symptoms (perceived stress (PSS-10), depression (PHQ-9), anxiety (GAD-7)) and QoL (IBDQ-32) scores were assessed at baseline. Logistic regression identified variables predicting a complicated IBD course at 12 months (composite outcome of need for escalation of biological/immunomodulator for disease relapse, recurrent corticosteroid use, IBD-related hospitalisation and surgery). Receiver operating characteristics (ROC) analysis identified optimal DSI thresholds predicting a complicated disease course and multivariable logistic regression assessed the risk of reaching this outcome. RESULTS: One hundred and seventy-two patients were recruited (100 Crohn's disease, 91 female). Median DSI was 21 (IQR 11-32) and 97 patients had endoscopically active disease at baseline. The DSI was significantly higher in patients with symptoms of moderate-severe stress (PSS-10 > 14, p < 0.01), depression (PHQ-9 ≥ 10, p < 0.01), anxiety (GAD-7 ≥ 10, p < 0.05) and impaired quality-of-life (IBDQ-32 < 168, p < 0.01). Only the baseline DSI (OR 1.05, p < 0.01) and endoscopically active disease (OR 6.12, p < 0.01) were associated with a complicated IBD course. A DSI > 23 was strongly predictive of a complicated IBD course (OR 8.31, p < 0.001). CONCLUSIONS: The DSI is associated with psychological distress, impaired QoL and predicts a more complicated disease course in patients with IBD.

The impact of disease activity on psychological symptoms and quality of life in patients with inflammatory bowel disease-results from the Stress, Anxiety and Depression with Disease Activity (SADD) Study.

BACKGROUND: Disease activity may be a risk factor for psychological illness in patients with inflammatory bowel disease (IBD). AIM: To correlate objective measures of disease activity with psychological symptoms. METHODS: Adult patients with IBD undergoing ileocolonoscopy were prospectively recruited. Demographic, psychological symptoms (depression, anxiety, stress), disease activity (symptoms, biomarkers, endoscopy), and quality of life (QoL) data were collected. One-way ANOVA and multivariable analyses examined the associations between disease activity and symptoms of psychological illness, and identified other predictors of mental illness and reduced QoL. RESULTS: A total of 172 patients were included, 107 with Crohn's disease (CD) and 65 with ulcerative colitis (UC). There was no significant association between objective disease activity (endoscopic scores, faecal calprotectin or C-reactive protein) and depression, anxiety or stress scores (P > 0.05 for all comparisons). Gastrointestinal symptoms were significantly associated with symptoms of depression, anxiety and stress in patients with CD and UC (P < 0.05). On multivariable analysis, only gastrointestinal symptoms were associated with severe symptoms of depression (OR 20.78 [6.71-92.37], P < 0.001) and anxiety (OR 4.26 [1.70-12.25], P = 0.004). Anti-TNF and corticosteroid use, the presence of severe depressive, moderate-severe stress and gastrointestinal symptoms, and endoscopically active IBD were associated with a reduced QoL (P < 0.05). Longer duration of IBD predicted an improved QoL (P < 0.05). CONCLUSIONS: Objective measures of disease activity are not associated with symptoms of psychological illness in patients with IBD. Clinicians should consider underlying mental illness in patients with IBD with active gastrointestinal symptoms.

Drainage of pancreatic fluid collections using a lumen-apposing metal stent with an electrocautery-enhanced delivery system.

BACKGROUND AND AIM: Our aim was to evaluate the efficacy and safety of a lumen-apposing metal stent with an electrocautery-enhanced delivery system (EDS-LAMS) for endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) in regular clinical practice. METHODS: A retrospective and subsequent prospective analysis was undertaken of all patients who underwent EUS-guided drainage of their PFCs using the EDS-LAMS at 17 tertiary therapeutic endoscopy centers. RESULTS: Two hundred eight cases of EDS-LAMS deployment were attempted in 202 patients (mean age 52.9 years) at time of evaluation. Ninety-seven patients had pancreatic pseudocysts (PPs), 75 walled-off pancreatic necrosis (WOPN), 10 acute peripancreatic fluid collections (APFCs), 6 acute necrotic collections (ANCs), and 14 postoperative collections (POCs). Procedural technical success was achieved in 202/208 cases (97.1%). Maldeployment occurred in 7/208 cases (3.4%). Clinical success was achieved in 142/160 (88.8%) patients (PP 90%, WOPN 85.2%, APFC 100%, ANC 75%, POC 100%). Delayed adverse events included stent migration in 15/202 (7.4%), stent occlusion and infection in 16/202 (7.9%), major bleeding in 4/202 (2%), and buried EDS-LAMS in 2/202 (1%). PFC recurrence occurred in 13/142 (9.2%) patients; 9/202 (4.5%) required surgical or radiological intervention for PFC management after EDS-LAMS insertion. CONCLUSIONS: This large international multicenter study evaluating the EDS-LAMS for drainage of PFCs in routine clinical practice suggests that the EDS-LAMS are safe and effective for drainage of all types of PFCs; however, further endoscopic therapy is often required for WOPN. Major bleeding was a rare complication in our cohort.

Increasing burden of advanced hepatocellular carcinoma in New Zealand-the need for better surveillance.

BACKGROUND: Regular surveillance for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B viral (HBV) infection and hepatitis C (HCV) cirrhosis improves survival by earlier detection of the cancer at an earlier stage when curative intervention may still be possible. We compared patient characteristics, surveillance history and outcomes in patients presenting with advanced HCC secondary to HBV and HCV. METHOD: In this retrospective study, clinical databases and notes were reviewed in all cases of advanced HCC related to HBV or HCV referred to the tertiary HCC service in Auckland, New Zealand between 1 January 2003 and 31 December 2017. RESULTS: Over the 15-year period, 368 patients were referred with advanced HCC secondary to HBV (HBV-HCC) and 278 secondary to HCV (HCV-HCC), representing over 50% of all cases of HCC cases secondary to viral hepatitis. Of these 646 patients with advanced HCC, 75% of patients were not receiving guideline-recommended surveillance. More patients with advanced HBV-HCC were diagnosed with HCC prior to the diagnosis of HBV, compared to patients with advanced HCV-HCC (40% vs 28%, p<0.01). Fewer patients with previously diagnosed HBV infection were undergoing HCC surveillance than patients with previously diagnosed HCV infection (26% vs 42%, p<0.01). Late diagnosed patients had the worst outcomes, with 88% receiving palliative care and surviving on average only seven months (HBV five months vs HCV eight months, p=0.05). CONCLUSION: Survival in New Zealanders with hepatocellular carcinoma remains poor because the cancer is incurable in most patients at the time of detection. Because most cases are secondary to chronic hepatitis B and C infections, improved screening and linkage to antiviral therapy and HCC surveillance should improve outcomes.

Exploring transition metal fluoride chelates - synthesis, properties and prospects towards potential PET probes.

The coordination chemistry of the first row transition metal trifluorides with terpy (2,2':6',2''-terpyridine) and Me3-tacn (1,4,7-trimethyl-1,4,7-triazacyclononane) was explored to identify potential systems for 18F radiolabelling. The complexes [MF3(L)] (M = Cr, Mn, Fe, Co; L = Me3-tacn, terpy) were synthesised and fully characterised by UV-vis and IR spectroscopy, microanalysis, and, for the diamagnetic [CoF3(L)], using 1H, 19F{1H} and 59Co NMR spectroscopy. Single crystal X-ray analyses are reported for [MF3(Me3-tacn)] (M = Mn, Co), [FeF3(terpy)] and [FeF3(BnMe2-tacn)]. Stability tests on [MF3(Me3-tacn)] (M = Cr, Mn, Fe) and [M'F3(terpy)] (M' = Cr, Fe) were performed and Cl/19F halide exchange reactions on [CrCl3(Me3-tacn)] using [Me4N]F in anhydrous MeCN solution, and [FeCl3(Me3-tacn)] using [Me4N]F in anhydrous MeCN or KF in aqueous MeCN solution were also carried out. Halide exchange reactions proved to be successful in forming [FeF3(Me3-tacn)] in aqueous MeCN solution within 30 minutes. Based upon the clean Cl/F exchange and the good stability observed for [FeF3(Me3-tacn)] in a range of competitive media, this was identified as a possible candidate for radiolabelling. 18F/19F isotopic exchange was achieved by addition of [18F]F- in the cyclotron target water to a MeCN solution of the benzyl-substituted analogue, [FeF3(BnMe2-tacn)], at a range of concentrations down to 24 nM with heating to 80 °C for 10 min.; the resulting [Fe18F19F2(BnMe2-tacn)] shows radiochemical purity (RCP) ≥90% after 2 h in a range of formulations, including 10% EtOH/phosphate buffered saline (PBS) and 10% EtOH/human serum albumin (HSA). This is the first reported complex with a transition metal directly bonded to [18F]F-.

Hepatitis B virus-related hepatocellular carcinoma presenting at an advanced stage: is it preventable?

AIM: Earlier diagnosis of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) increases treatment options and survival. The aim of this study is to evaluate which factors are associated with late presentation of HBV-related HCC. METHOD: This is a retrospective review of all cases of HBV-related HCC diagnosed with late-stage/incurable HCC in New Zealand between 2003 and 2017. Cases were defined as patients with a positive hepatitis B surface antigen (HBsAg), and advanced (not amenable to potentially curable treatments) HCC at initial diagnosis. Patients were categorised into four groups according to potential reasons for late presentation: no previous diagnosis of HBV infection (Group A); known HBV diagnosis but not receiving HCC surveillance (Group B); known HBV diagnosis and receiving suboptimal HCC surveillance (Group C); and known HBV diagnosis and receiving optimised HCC surveillance (Group D). RESULTS: A total of 368 patients were reviewed. The average age at death was 59 years, and the majority of patients were Maori (39%), Pacific (34%) or Asian (20%). The incidence of patients presenting with HBV-related advanced HCC increased from 4.5 cases to 6.3 cases per million people over the review period. Of the cases, 40% were categorised into Group A, 26% into Group B, 12% into Group C and 23% in Group D. Overall, the median survival was 138 days, and this did not change during the study period. Patients receiving optimised surveillance (Group D) survived longer (mean 469 days) than patients in Group A (90 days), Group B (145 days) or Group C (152 days) (p<0.05). Patients in Group D were more likely to be treated with transarterial chemoembolisation than patients in other groups (40% vs 15%, p<0.05). CONCLUSION: This study has highlighted the need for improved rates of HBV diagnosis, better follow-up of those infected and the importance of optimal HCC surveillance. In New Zealand, HBV-related HCC disproportionately affects minority ethnic groups, and given the increasing incidence, provides a potential domain to reduce health inequities.

Addressing patient alcohol use: a view from general practice.

INTRODUCTION: General practitioners (GPs) have the potential to promote alcohol harm minimisation via discussion of alcohol use with patients, but knowledge of GPs' current practice and attitudes on this matter is limited. Our aim was to assess GPs' current practice and attitudes towards discussing alcohol use with their patients. METHODS: This qualitative study involved semi-structured, face-to-face interviews with 19 GPs by a group of medical students in primary care practices in Wellington, New Zealand. FINDINGS: Despite agreement amongst GPs about the importance of their role in alcohol harm minimisation, alcohol was not often raised in patient consultations. GPs' usual practice included referral to drug and alcohol services and advice. GPs were also aware of national drinking guidelines and alcohol screening tools, but in practice these were rarely utilised. Key barriers to discussing alcohol use included its societal 'taboo' nature, time constraints, and perceptions of patient dishonesty. CONCLUSION: In this study there is a fundamental mismatch between the health community's expectations of GPs to discuss alcohol with patients and the reality. Potential solutions to the most commonly identified barriers include screening outside the GP consultation, incorporating screening tools into existing software used by GPs, exploring with GPs the social stigma associated with alcohol misuse, and framing alcohol misuse as a health issue. As it is unclear if these approaches will change GP practice, there remains scope for the development and pilot testing of potential solutions identified in this research, together with an assessment of their efficacy in reducing hazardous alcohol consumption.