Surveillance of enteropathogenic bacteria, protozoa and helminths in travellers returning from the tropics.

Diarrhoea is a frequent symptom associated with travelling to tropical regions, but the cause is often not found. Epidemiology was assessed including up-to-date real-time PCR approaches.We analysed datasets of 528 patients who presented at the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany, between 2006 and 2010 for screening purposes or because of diarrhoea. Stool samples were obtained and investigated by microscopy, bacterial culture, two PCR assays targeting Entamoeba histolytica, Entamoeba dispar, Giardia duodenalis, and Cryptosporidium parvum, or Salmonella spp., Shigella/EIEC spp., Campylobacter jejuni, and Yersinia spp.Among patients with gastrointestinal symptoms, 51% tested positive for bacteria or parasites, of which 66% had a known enteropathogenic potential. In patients without diarrhoea, 53% (n = 80) were positive, and 33% of these cases harboured agents of pathogenic potential. Association with clinical symptoms was primarily found for bacterial infections. Blastocystis hominis, however, was more frequent in asymptomatic than in symptomatic travellers.In conclusion, the study stresses the etiological relevance of bacterial gastroenteritis in travellers returning from the tropics, the need for molecular approaches to increase diagnostic sensitivity and demonstrates that asymptomatic carriage of enteropathogens after prolonged stays in the tropics is similarly frequent compared with symptomatic infections in travellers.

Vaccination against Japanese encephalitis with IC51: systematic review on immunogenicity, duration of protection and safety.

Japanese encephalitis is a disease caused by a flavivirus which is transmitted by mosquitos in endemic countries. Considering the potentially severe outcomes of the disease, vaccination is recommended for those at risk of exposure. During recent years, IC51 (IXIARO®, JESPECT®, JEVAL®) has increasingly been used to protect travellers from Europe and the USA. However, no systematic review exists that summarizes the currently available evidence on the immunogenicity and safety of this vaccine. We conducted a systematic review on the immunogenicity and safety of IC51, using the databases PubMed, MEDLINE, EMBASE and ClinicalTrials.gov (search date: 31 August 2019). Data extracted from included studies were grouped by outcomes and stratified by population and setting. Risk of bias (ROB) was assessed using the RoB 2 tool for randomized controlled trials (RCTs) and ROBINS-I for non-randomized studies. Due to high heterogeneity, meta-analysis was not performed. A total of 32 studies from 16 countries met the inclusion criteria (15 RCTs, 17 non-randomized studies). ROB was serious or high in the majority of studies. Seroprotection rates ranged from 93 to 100% in adults (seven studies) and from 91 to 100% in children (four studies). In the study involving adults aged 64 years and older, seroprotection was 65% with higher rates in persons who were previously vaccinated against tick-borne encephalitis virus. Safety was investigated in 27 studies. Rates of serious adverse events were below 5% in all age groups, with the majority not being causally related to the vaccine. IC51 is a safe vaccine with good seroprotective abilities in persons aged >2 months to <64 years. The body of evidence, however, is weakened by a large amount of heterogeneity in study and clinical trial methodology. Further well-designed RCTs with special risk groups are needed.

[Travel vaccinations for certain groups of persons]. / Reiseimpfungen für besondere Personengruppen.

The number of international travelers has been continuously increasing in recent decades. Among travelers, there are more and more people at an increased risk for acquiring diseases that could be prevented by vaccines or for the development of a severe course of disease. Risk groups in travel medicine are senior travelers, children, pregnant and breast-feeding women, persons with pre-existing medical conditions, and persons who visit their friends and relatives abroad (VFR). Individuals in these groups require attention during pretravel advice consultations, particularly with regards to recommended vaccinations. On the other hand, for some risk groups, particular vaccines cannot be given for safety reasons or because the response to vaccines is reduced. Not all risk groups or each vaccine have sufficient evidence available, so each patient's risks and benefits must be weighed during pretravel consultation. In this article, the particularities for each risk group with respect to pretravel immunization are highlighted.

Diagnosis and Management of Systemic Endemic Mycoses Causing Pulmonary Disease.

Systemic endemic mycoses cause high rates of morbidity and mortality in certain regions of the world and the real impact on global health is not well understood. Diagnosis and management remain challenging, especially in low-prevalence settings, where disease awareness is lacking. The main challenges include the variability of clinical presentation, the fastidious and slow-growing nature of the fungal pathogens, the paucity of diagnostic tests, and the lack of options and toxicity of antifungal drugs. Coccidioidomycosis and paracoccidioidomycosis are restricted to the Americas only, and while histoplasmosis and blastomycosis also occur predominantly in the Americas, these mycoses have also been reported on other continents, especially in sub-Saharan Africa. Talaromycosis is endemic in tropical and subtropical regions in South-East Asia and southern China. Systemic endemic mycoses causing pulmonary disease are usually acquired via the airborne route by inhalation of fungal spores. Infections can range from asymptomatic or mild with flu-like illnesses to severe pulmonary or disseminated diseases. Skin involvement is frequent in patients with paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis and manifests as localized lesions or diffuse nodules in disseminated disease, but can also occur with other endemic mycoses. Culture and/or characteristic histopathology from clinical samples is the diagnostic standard for endemic mycoses. Immunological assays are often not available for the diagnosis of most endemic mycoses and molecular amplification methods for the detection of fungal nucleic acids are not standardized at present. The first-line treatment for mild to moderate histoplasmosis, paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis is itraconazole. Severe illness is treated with amphotericin B. Patients with severe coccidioidomycosis should receive fluconazole. Treatment duration depends on the specific endemic mycosis, the severity of disease, and the immune status of the patient, ranging between 6 weeks and lifelong treatment.

Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial.

BACKGROUND: Lyme borreliosis develops in 1-5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings. METHODS: In this randomised, double-blind, placebo-controlled, multicentre trial done in 28 study sites in Germany and Austria, adults were equally assigned to receive topical 10% azithromycin or placebo twice daily for 3 consecutive days, within 72 h of a tick bite being confirmed. Randomisation numbers, which were stratified by study site, were accessed in study centres via an interactive voice-response system, by pharmacists not involved in the study. The primary outcome was the number of treatment failures, defined as erythema migrans, seroconversion, or both, in participants who were seronegative at baseline, had no further tick bites during the study, and had serology results available at 8 weeks (intention-to-treat [ITT] population). This study is registered with EudraCT, number 2011-000117-39. FINDINGS: Between July 7, 2011, and Dec 3, 2012, 1371 participants were randomly assigned to treatment, of whom 995 were included in the ITT population. The trial was stopped early because an improvement in the primary endpoint in the group receiving azithromycin was not reached. At 8 weeks, 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure (odds ratio 0·97, 95% CI 0·42-2·26, p=0·47). Topical azithromycin was well tolerated. Similar numbers of patients had adverse events in the two groups (175 [26%] of 505 vs 177 [26%] of 490, p=0·87), and most adverse events were mild. INTERPRETATION: Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks. FUNDING: Ixodes AG.

Pilot study on the internal exposure to heavy metals of informal-level electronic waste workers in Agbogbloshie, Accra, Ghana.

Informal-level electronic waste (e-waste)-processing activities are performed at hotspots in developing countries such as India, China, and Ghana. These activities increase the ambient burden of heavy metals and contribute to the toxic exposure of the general population. However, few data exist on the internal exposure of populations involved in these informal activities and in close contact with fumes from the direct combustion of electronic waste products in these countries. Therefore, in a cross-sectional study design, we analyzed blood, urine, and hair samples from 75 e-waste workers residing in and/or working on a large e-waste recycling site in Agbogbloshie, Accra, Ghana, and compared the results against those of 40 individuals living in a suburb of Accra without direct exposure to e-waste recycling activities. A comparative analysis using the Mann-Whitney U test showed significantly higher median concentrations of blood lead (88.5 vs. 41.0 µg/l, p < 0.001), cadmium (0.12 vs. 0.10 µg/gcrea, p = 0.023), chromium (0.34 vs. 0.23 µg/gcrea, p < 0.001), and nickel (3.18 vs. 2.03 µg/gcrea, p < 0.001) in the urine of e-waste workers than those of controls. There was no difference in blood cadmium concentrations between the groups (0.51 vs. 0.57 µg/l, p = 0.215) or in urine mercury levels (0.18 vs. 0.18 µg/gcrea, p = 0.820). Hair mercury levels were higher in the controls than in the e-waste workers (0.43 vs. 0.72, p < 0.001). We compared our data with those from European populations, specifically using the German reference values, and found that the internal concentrations of the participants exceeded the German reference values in 59.3 vs. 3.1% (e-waste workers vs. controls) for blood lead, 56.9 vs. 52.5% for urine nickel, 22.2 vs. 20.0% for urine chromium, and 17.8 vs. 62.2% for hair mercury. In particular, the high blood lead levels of up to several hundred micrograms per liter are a cause for concern because many of the workers in Agbogbloshie are children or adolescents who are in developmental stages and are at a particular risk for negative health effects. We conclude that exposure to some of the heavy metals tended to be a citywide phenomenon, but populations directly exposed to e-waste recycling are experiencing higher exposure levels and have concentration levels much higher than those of the general population and much higher than those found in European populations. To achieve environmental sustainability and to minimize the impact of e-waste-processing activities in developing countries, national authorities must formalize the rapidly growing informal-level e-waste management sector in these countries by deploying cleaner and easy-to-operate e-waste processing technologies.

Immunogenicity and safety of the inactivated Japanese encephalitis vaccine IXIARO® in elderly subjects: Open-label, uncontrolled, multi-center, phase 4 study.

BACKGROUND: IXIARO® is a Vero cell-derived, inactivated Japanese encephalitis (JE) vaccine licensed mainly in western countries for children and adults traveling to JE endemic areas. Limited immunogenicity and safety data in elderly travelers have been available. OBJECTIVES: To evaluate safety and immunogenicity of IXIARO in elderly subjects. METHODS: Open-label, single arm, multi-centered study. Two-hundred subjects with good general health, including adequately controlled chronic conditions, received two doses of IXIARO®, 28days apart. Protective levels of antibodies were tested 42days after the second dose. Systemic and local adverse events (AEs) were solicited for 7days after each dose, unsolicited AEs were collected up to day 70 and in a phone call at month 7. SUMMARY OF RESULTS: Subjects were aged 64-83years (median 69.0years). Nineteen percent of subjects had serious or medically attended AEs up to Day 70 (primary endpoint), none of them causally linked to IXIARO. Solicited local AEs were reported by 33.5% (most common: local tenderness) and solicited systemic AEs by 27% (most common: headache) of subjects. The seroprotection rate was 65% with a geometric mean titre (GMT) of 37. Subjects with tick borne encephalitis (TBE) vaccinations in the past 5years (N=29) had a SCR of 90% and GMT of 65. CONCLUSIONS: IXIARO is generally well tolerated in the elderly, and the safety profile is largely comparable with younger adults. SCR and GMT are lower compared to younger adults, but SCR is in the range reported in elderly for other vaccines e.g. against TBE, hepatitis-A virus (HAV)/hepatitis-B virus (HBV), influenza. The differences in SCR and GMT from younger to elderly adults were in the range of other vaccines. Duration of protection is uncertain in older persons, therefore a booster dose (third dose) should be considered before any further exposure to JE virus.

Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial.

Background. Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients. Methods. We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks. Results. Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 ± 16.5 years and 231 patients aged 56.5 ± 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55-1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation. Conclusions. We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment. ClinicalTrials.gov Identifier. NCT01143272.

Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis.

BACKGROUND: Dengue fever (DF) is one of the most relevant human arboviral infections worldwide and has become a frequent cause of fever in the returning traveller. This retrospective study aimed to characterize epidemiological and clinical features and laboratory findings of dengue fever in German travellers. METHODS: This descriptive study analyzed medical records of patients diagnosed with DF presenting at the Section of Tropical Medicine of the University Medical Centre Hamburg-Eppendorf from 2007 to 2011. Data were collected and analyzed retrospectively. RESULTS: In total, data of 119 DF patients (52 female, 67 male) were included in this study. The median age of the patients was 35 (range 15-75 years). DF was most frequently acquired in South-East Asia (n = 65; 54.7%), and in particular in Thailand (n = 23; 19.7%). A considerable percentage of DF infections (n = 14; 11.8%) was imported from Africa. Patients predominantly presented with fever, headache, rash, myalgia and arthralgia but also with gastrointestinal symptoms, i.e. diarrhoea. Nine patients showed signs of minor haemorrhagic manifestations. Neurological complications occurred in 13 patients. Low platelet count, leukopenia and elevated liver enzymes were the most relevant laboratory findings. Twenty patients (17.8%) had to be hospitalized. Overall, the clinical course was mostly mild to moderate, 13 patients (10.9%) showed DF warnings signs, no fatalities occurred. CONCLUSIONS: DF presented as a mostly mild to moderate disease in this study cohort. Outpatient treatment was adequate for the majority of patients. Still, detailed knowledge of clinical symptoms and laboratory features is essential for appropriate triage.

Helicobacter pylori Infection Is Associated with Higher CD4 T Cell Counts and Lower HIV-1 Viral Loads in ART-Naïve HIV-Positive Patients in Ghana.

BACKGROUND: Worldwide, there is a high co-endemicity of HIV and H. pylori infection and there is growing evidence that H. pylori co-infection is associated with parameters of HIV disease progression. The objective of this study was to investigate the prevalence of H. pylori infection, and the association with clinical, immunological and virological parameters in a large cohort of HIV-infected individuals and uninfected controls in a West African country. METHODS: HIV-patients (n = 1,095) and HIV-negative individuals (n = 107) were recruited at a university hospital in Ghana. H. pylori status was determined using stool antigen testing. HIV-related, clinical and socio-demographic parameters were recorded and analyzed according to H. pylori status. RESULTS: The prevalence of H. pylori infection was significantly lower in HIV-positive compared to HIV-negative individuals (51.5 vs. 88%, p<0.0001). In HIV patients, H. pylori prevalence decreased in parallel with CD4+ T cell counts. In ART-naïve HIV-infected individuals, but not in those taking ART, H. pylori infection was associated with higher CD4 cell counts (312 vs. 189 cells/µL, p<0.0001) and lower HIV-1 viral loads (4.92 vs. 5.21 log10 copies/mL, p = 0.006). The findings could not be explained by socio-demographic confounders or reported use of antibiotics. Having no access to tap water and higher CD4+ T cell counts were identified as risk factors for H. pylori infection. CONCLUSIONS: H. pylori prevalence was inversely correlated with the degree of immunosuppression. In ART-naïve individuals, H. pylori infection is associated with favorable immunological and virological parameters. The underlying mechanisms for this association are unclear and warrant investigation.

Serological response following re-vaccination with Salmonella typhi Vi-capsular polysaccharide vaccines in healthy adult travellers.

An injectable Vi-capsular polysaccharide vaccine against typhoid fever is available but vaccine-induced immunity tends to wane over time. The phenomenon of immunotolerance or hyporesponsiveness has earlier been described for polysaccharide vaccines such as pneumococcal capsular polysaccharide vaccine and some publications also suggest a possible immunotolerance after revaccination with Vi-capsular polysaccharide vaccines. In this study, post-immunisation antibody concentrations in adult travellers first vaccinated with a Salmonella typhi Vi-capsular polysaccharide vaccine (primary vaccination group) were compared with those having received one or more vaccinations previously (multiple vaccinations group). Vaccines administered were Typherix(®) (GlaxoSmithKline), Typhim Vi(®) (Sanofi Pasteur MSD) or Hepatyrix(®) (GlaxoSmithKline). Blood samples were obtained prior to vaccination (day 0) and on day 28 (-1/+14) after vaccination. Serum Vi-Antigen IgG concentrations were measured by ELISA. Of the 85 subjects included in the per protocol data set, 45 (53%) belonged to the multiple vaccinations group. In both groups, geometric mean antibody concentrations (GMCs) were significantly higher after vaccination than before vaccination. Pre-vaccination GMCs were lower in the primary vaccination group than in the multiple vaccinations group (3.40 µg/ml versus 6.13 µg/ml, P=0.005), while there was no significant difference in the post vaccination GMCs between groups (11.34 µg/ml versus 14.58 µg/ml, P=0.4). In the multiple vaccinations group, vaccination was performed 18 to 57 months after the last vaccination (median 38 months) and there was a negative correlation between time since last vaccination and antibody concentration on day 0. In conclusion, we were not able to demonstrate a relevant immunotolerance after multiple versus primary vaccination with S. typhi Vi-capsular polysaccharide vaccines.

Helicobacter pylori Coinfection Is Associated With Decreased Markers of Immune Activation in ART-Naive HIV-Positive and in HIV-Negative Individuals in Ghana.

BACKGROUND: Helicobacter pylori coinfection in human immunodeficiency virus (HIV) patients has been associated with higher CD4+ cell counts and lower HIV-1 viral loads, with the underlying mechanisms being unknown. The objective of this study was to investigate the impact of H. pylori infection on markers of T-cell activation in HIV-positive and HIV-negative individuals. METHODS: In a cross-sectional, observational study, HIV patients (n = 457) and HIV-negative blood donors (n = 79) presenting to an HIV clinic in Ghana were enrolled. Data on clinical and sociodemographic parameters, CD4+/CD8+ T-cell counts, and HIV-1 viral load were recorded. Helicobacter pylori status was tested using a stool antigen test. Cell surface and intracellular markers related to T-cell immune activation and turnover were quantified by flow cytometry and compared according to HIV and H. pylori status. RESULTS: Helicobacter pylori infection was associated with decreased markers of CD4+ T-cell activation (HLA-DR+CD38+CD4+; 22.55% vs 32.70%; P = .002), cell proliferation (Ki67; 15.10% vs 26.80%; P = .016), and immune exhaustion (PD-1; 32.45% vs 40.00%; P = .005) in 243 antiretroviral therapy (ART)-naive patients, but not in 214 patients on ART. In HIV-negative individuals, H. pylori infection was associated with decreased frequencies of activated CD4+ and CD8+ T cells (6.31% vs 10.40%; P = .014 and 18.70% vs 34.85%, P = .006, respectively). CONCLUSIONS: Our findings suggest that H. pylori coinfection effectuates a systemic immune modulatory effect with decreased T-cell activation in HIV-positive, ART-naive patients but also in HIV-negative individuals. This finding might, in part, explain the observed association of H. pylori infection with favorable parameters of HIV disease progression. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT01897909.

A 2013/2014 northern hemisphere season surface antigen inactivated trivalent influenza vaccine--Assessing the immunogenicity and safety in an open label, uncontrolled study.

The present study evaluated the safety and immunogenicity of the 2013/2014 trivalent surface antigen inactivated subunit seasonal influenza virus vaccine Fluvirin® in healthy adults (18 - ≤ 60 years) and elderly (>60 years). The vaccine contained 15 µg haemagglutinin protein from each of influenza A/California/7/2009 (H1N1)pdm09-like strain, A/Victoria/361/2011 (H3N2)-like strain and B/Massachusetts/2/2012-like strain (B/Yamagata) as recommended by the WHO in the 2013/2014 Northern Hemisphere season. Antibody response to each influenza antigen after vaccination was measured prior to vaccination and 21 d after by single radial hemolysis (SRH) assay or hemagglutination inhibition (HI) assay in accordance with Guidance CPMP/BWP/214/96. 125 subjects (61 adults and 64 elderly) were enrolled in the study. Pre-vaccination protective antibody levels (SRH area ≥ 25 mm(2)) against A(H1N1), A(H3N2) and the B strain were detected in 17%, 20% and 57% of adults and in 36%, 20% and 55% of elderly, respectively, Post-vaccination, SRH area ≥ 25 mm(2) was detectable in 95%, 82% and 92% in adult and in 80%, 84% and 92% of the elderly subjects for A(H1N1), A(H3N2) and the B strain, respectively. Geometric mean ratio (GMR) was higher in adult subjects (2.62-7.62) than in elderly subjects (2.33-3.42). All three CHMP licensure criteria were met for all strains contained in the vaccine for both age groups. The most frequently reported solicited local and systemic reactions were pain at the injection side, headache and fatigue. In conclusion, the vaccine demonstrated a good immunogenicity and an acceptable safety profile in both adults and elderly.