Philipp Hotz

Hepatitis E, Helicobacter pylori, and gastrointestinal symptoms in workers exposed to waste water

Background: Workers exposed to sewage may have an increased risk of infection by Helicobacter pylori and hepatitis E virus (HEV). Aims: To assess the prevalence of clinical hepatitis E (HE) and peptic ulcer disease as well as the seroprevalence of antibodies to H pylori and HEV in workers with and without sewage exposure and to look for symptoms due to exposure to endotoxin. Methods: In the first year of a prospective cohort study 349 sewage exposed workers and 429 municipal manual workers (participation: 61%) underwent a complete medical examination. Travelling to endemic areas, socioeconomic level, age, country in which childhood was spent, and number of siblings were considered as the main confounding factors. Results: Peptic ulcer disease and clinical HE did not occur more often in workers exposed to sewage. Prevalence of antibodies to HEV was 3.3% and overall prevalence of IgG antibodies to H pylori was 42% with large differences between subgroups. Logistic regression did not show an increased risk of seropositivity or antibodies to parietal cells in sewage exposed workers, but disentangling the effect of exposure from that of confounders was extremely difficult. No increase of symptoms due to exposure to endotoxin was found in sewage workers, with the exception of diarrhoea. Conclusions: No clear increased risk of infection by H pylori or by HEV in workers exposed to sewage was found in this cross-sectional study, but these results need to be confirmed by follow up.

High occurrence of hepatitis E virus in samples from wastewater treatment plants in Switzerland and comparison with other enteric viruses

Hepatitis E virus (HEV) is responsible for many enterically transmitted viral hepatitides around the world. It is currently one of the waterborne diseases of global concern. In industrialized countries, HEV appears to be more common than previously thought, even if it is rarely virulent. In Switzerland, seroprevalence studies revealed that HEV is endemic, but no information was available on its environmental spread. The aim of this study was to investigate -using qPCR- the occurrence and concentration of HEV and three other viruses (norovirus genogroup II, human adenovirus-40 and porcine adenovirus) in influents and effluents of 31 wastewater treatment plants (WWTPs) in Switzerland. Low concentrations of HEV were detected in 40 out of 124 WWTP influent samples, showing that HEV is commonly present in this region. The frequency of HEV occurrence was higher in summer than in winter. No HEV was detected in WWTP effluent samples, which indicates a low risk of environmental contamination. HEV occurrence and concentrations were lower than those of norovirus and adenovirus. The autochthonous HEV genotype 3 was found in all positive samples, but a strain of the non-endemic and highly pathogenic HEV genotype I was isolated in one sample, highlighting the possibility of environmental circulation of this genotype. A porcine fecal marker (porcine adenovirus) was not detected in HEV positive samples, indicating that swine are not the direct source of HEV present in wastewater. Further investigations will be necessary to determine the reservoirs and the routes of dissemination of HEV.

Cadmium or cadmium compounds and chronic kidney disease in workers and the general population: a systematic review

Abstract Background: Cadmium (Cd) is abundantly documented as a metal mainly affecting tubular function both in workers and in the general population indirectly exposed via the environment. Results from epidemiological studies linking Cd exposure and risk of progression to chronic kidney disease (CKD) are, however, conflicting. Objectives: To perform a systematic review of the association between Cd exposure and CKD. Methods: A systematic appraisal of publications found in MEDLINE (1946–2014), EMBASE (1974–2012) and an in-house database (1986–2013) was conducted. Additional studies were searched for by contacting experts and checking reference lists. Search terms used key and text words. No language restriction was applied. Cohort, case–control and case-series with follow-up including individual and objective assessment of occupational or environmental exposure were eligible. Studies were selected and data extracted by two independent reviewers using predefined forms. Study characteristics and results were extracted to structured tables. Synthesis was qualitative and results appraised with causality criteria. Results: Thirty-four exposed groups, totaling more than 3000 participants, were eligible. Overall, results disclosed no convincing evidence supporting a risk of progression to CKD in populations exposed to Cd. Lack of information about methods, risk of bias and heterogeneity were identified as limitations and precluded conducting a meta-analysis. Publication bias did not appear as a major problem. Conclusions: This qualitative systematic review does not support the contention that human exposure to Cd leads to progressive CKD.

Hepatitis E, Helicobacter pylori, and peptic ulcers in workers exposed to sewage: a prospective cohort study

Background: Workers exposed to sewage may have an increased risk of infection by Helicobacter pylori and hepatitis E virus (HEV). Objectives: To assess the incidence of clinical hepatitis E and peptic ulcers and the seroconversion rate of antibodies to H pylori and HEV in workers with and without sewage exposure. Methods: 332 workers exposed to sewage and a control group of 446 municipal manual workers (61% participation rate) entered a prospective cohort study with clinical examination and determination of antibodies to H pylori and HEV (immunoglobulins G and A or G and M, respectively). Survival curves were examined with log rank tests and Cox regressions. Travelling to endemic areas, socioeconomic level, age, country of childhood, number of siblings, and personal protective equipment were considered as the main confounding factors. Results: Incidence of clinical hepatitis E was not increased in sewage workers. One peptic ulcer and three eradications were recorded in sewage workers compared with no peptic ulcers and 12 eradications in control workers. Incidence rates of approximately 0.01, 0.10, and 0.15 seroconversion/person-year for hepatitis E, H pylori IgG and H pylori IgA, respectively, were found in both exposed and non-exposed workers. Survival curves did not show an increased risk in sewage workers and no association with any exposure indicator was found. Sensitivity analyses did not alter these results. Conclusions: Sewage does not appear to be a source of occupational infection by H pylori or HEV in trained sewage workers with personal protective equipment working in a region with good sanitation.

Can serum cytokine profile discriminate irritant-induced and allergen-induced symptoms? A cross-sectional study in workers mostly exposed to laboratory animals

Background In workers exposed mostly to laboratory animals (LA), symptoms may be due to irritants or allergens. Correct aetiological diagnosis is important for health surveillance. Objectives This study aims to test whether work-related (WR) allergen-induced symptoms are associated with a cytokine profile distinct from that due to irritants. Methods In a cross-sectional study (n=114), WR respiratory and/or skin symptoms were assessed through a standardised clinical examination and sensitisation to rat and/or mouse allergen determined by serum immunoglobulin E. Serum cytokine concentrations were measured by multiplex assays. The predefined cytokine profiles ‘sensitiser’ (interleukin (IL)-4, IL-5, IL-13, eotaxin-1) and ‘irritation’ (IL-8, IL-17A, IL-17F, IL-22) were considered positive, when ≥3 concentrations exceeded the 95th percentile of the asymptomatic non-sensitised group. Results were examined by hierarchical clustering analyses (HCA) and multiple linear regression. Explorative analyses were carried out for nine additional cytokines. Exposure to allergens and endotoxin was assessed in a subpopulation. Results The prevalence of the profile ‘irritation’ was comparable in 28 symptomatic non-sensitised workers and 71 asymptomatic non-sensitised workers. HCA showed that nearly all symptomatic non-sensitised workers were gathered in two subclusters, characterised by high IL-17A levels, but different IL-8 levels. Multiple linear regression identified drug consumption and current complaints as confounders. Sensitised subjects were too few (n=14) for testing the profile ‘sensitiser’. Conclusions In this unselected population of LA workers, the profile ‘irritation’ did not prove to be a valuable health surveillance tool. Low power precluded assessment of the profile ‘sensitiser’. The increased IL-17A concentration may originate from irritative constituents of organic dust.

Response to letter to the editor from Elinder and Nordberg concerning Byber et al. 2016. Cadmium or cadmium compounds and chronic kidney disease in workers and the general population: a systematic review, Crit Rev Toxicol. 46(3):191-240. DOI: 0.3109/10408444.2015.1076375.

We are grateful for the opportunity to answer the letter by C.G. Elinder and G.F. Nordberg (2017) that raises interesting points. To meet the requested format of this response, we included here below the reference to the pages of the published paper rather than reproducing extracts. It is quite right that the criteria for classifying chronic kidney disease (CKD) into categories as defined nowadays [categories G1 to G5 and A1 to A3] were not in use when the first publications about cadmium-induced kidney disease were published. However, these current categories should not be confused with the definition of the disease characteristics or markers currently considered robust for diagnosing CKD (hematuria and hypertension, markers of glomerular filtration, proteinuria or albuminuria, histopathology) (Byber et al. 2016, p. 192–194). In other words, the literature search has not been restricted to publications applying the current CKD categorizing criteria, but used disease characteristics or markers currently considered robust for diagnosing CKD (Byber et al. 2016, p. 195). This was indispensable to avoid the problem of “chronic renal confusion” resulting from using different CKD definitions and a disturbing plethora of laboratory markers with ambiguous or unknown clinical significance (Byber et al. 2016, p. 192–193). The objective of our review was not to assess whether authors used the best criteria at the time their study was conducted, but to assess whether the evidence of a link with CKD (defined with criteria considered as robust and sound) and Cd exposure is currently available. These clinical characteristics and laboratory markers of disease (urea, creatinine, proteinuria) were well-known in the oldest studies (Byber et al. 2016, p. 212–213 and 223) and we indicated for each study whether changes in proteinuria and/ or GFR had occurred regardless of the current categorizing criteria (Table 1). The problem that could not be solved was a re-interpretation of pooled laboratory findings in the light of the current categorizing criteria. Indeed, a meta-analysis was impossible (Byber et al. 2016, p. 227–228). However, the changes concerning proteinuria and/or markers of GFR in each individual study between baseline and last examination did not indicate a consistent increase (Byber et al. 2016, p. 220, Tables S1–S34). To summarize, the current categories of the CKD classification were neither a search term nor an inclusion criterion and the disease characteristics currently considered sound for diagnosing CKD were already in use at the time of the oldest publications. Regarding the Swedish studies (J€arup et al. 1993, 1995), Elinder and Nordberg do not mention that the measurements they report did not show clear evidence of a decrease in measured GFR. The decrease was very small (<2.5ml/min/ 1.73m) and of doubtful clinical significance at best. This “decrease” was not confirmed by the three GFR estimates used in this study and not confirmed at the longest followup. Furthermore, a presentation bias may have been an issue (Byber et al. 2016, p. 209, 221 and 224). Finally, according to the outcome selected in our study (Byber et al. 2016, p. 195), the crucial point was GFR measurement, because it is considered the best overall index of kidney function (Byber et al. 2016, p. 193). It was measured with a reliable method (CrEDTA clearance) and the association with the “degree of tubular damage” was non-relevant for the purpose of our study. Lastly, in our opinion, kidney stones are not a typical form of CKD, and this information was, therefore, not discussed in depth (as in all other studies reporting kidney stones). The results summarized by Piscator (1984) had a fairly high risk of bias requiring very cautious interpretation (Byber et al. 2016, p. 209–210 and 223–224). As explicitly stated, ecological studies were not included in the systematic review (Byber et al. 2016, p. 194–195). A change in the inclusion criteria is imaginable but cannot be restricted to the study by Hellstr€ om et al. (2001) only. The other ecological studies would have to be considered as well for being able to assess the whole evidence (Byber et al. 2016, p. 218–219). Moreover, it cannot be ignored that the confidence interval in the publication by Hellstr€ om et al. (2001) was extremely wide and even compatible with a protective effect of cadmium exposure (Byber et al. 2016, p. 211). Furthermore, the exposure indicator was not reliable, which was reported by the same authors in a second publication (Hellstr€ om et al. 2004; Byber et al. 2016, p. 211 and 227). The occupational mortality studies mentioned by Elinder and Nordberg were discussed (Byber et al. 2016, p. 211). Of note, publications pertaining to the same population cannot be cited as independent studies and the evidence from the most recent and/or most detailed studies should be presented. With respect to publications by Nishijo et al. (2017) cited by Elinder and Nordberg, the inclusion criteria are again the decisive point. Studies were either excluded because they did not fulfill the inclusion criteria or were included. However, in