[Need for improvement in the care of patients with Clostridioides difficile infections (CDI) - expert opinion in international comparison]. / Verbesserungsbedarf in der Versorgung von Patienten/-innen mit Clostridioides-difficile-lnfektionen (CDI) ­ Experten/-innenmeinung im internationalen Vergleich.

INTRODUCTION: Clostridioides difficile infection (CDI), as a nosocomial disease, is associated with high morbidity and mortality. Even though the incidence of CDI has been declining in Germany in recent years, the individual infection may pose a medical challenge despite therapeutic advances. The aim here is to clarify which gaps practitioners consider to be particularly serious in care and in the existing evidence base. METHODS: In a moderated workshop of German CDI experts the topics considered as relevant were identified. A survey already conducted in five other countries (Australia, France, Great Britain, Canada, and Italy) was adapted and processed by 27 practitioners. During the evaluation, the topics perceived as particularly important were identified, the statements of the specialist groups were compared and changes in opinion were considered. RESULTS: 27 fully completed questionnaires were evaluated. The need for improvement was primarily seen in the prevention of CDI recurrences (74.1%) and the treatment of recurrences (55.6%). Evidence deficits were noted in the treatment of recurrences (55.6%) and identification of risk factors for recurrences (48.1%). Improving care via fecal microbiota transfer (FMT) was named by 70.4%. For guidelines, more clarity (48.1%) and more regular updates (40.7%) were desired. For patients, better education on appropriate antibiotic use (52.0%) and choice of FMT were desired (48.1%). SUMMARY: The German expert view and the international assessment is similar, when asked about the need for improvement in care and evidence gaps in the treatment of patients with CDI: The focus is on prevention and therapy of recurrent CDI. The problem of access to FMT is a German peculiarity that seems to need improvement.

Trends in the epidemiology of Clostridioides difficile infection in Germany.

PURPOSES: Despite reports of a declining incidence over the last decade, Clostridioides difficile infection (CDI) is still considered the most important healthcare-associated causes of diarrhea worldwide. In Germany, several measures have been taken to observe, report, and influence this development. This report aims to analyze the development of hospital coding for CDI in Germany over the last decade and to use it to estimate the public health burden caused by CDI. METHODS: Reports from the Institute for Hospital Remuneration Systems, German Federal Statistical Office (DESTATIS), the Robert-Koch-Institute (RKI), Saxonian authorities and hospital quality reports during 2010-2021 were examined for CDI coding and assessed in a structured expert consultation. Analysis was performed using 2019 versions of Microsoft Excel® and Microsoft Access®. RESULTS: Peaks of 32,203 cases with a primary diagnosis (PD) of CDI and 78,648 cases with a secondary diagnosis (SD) of CDI were observed in 2015. The number of cases had decreased to 15,412 PD cases (- 52.1%) and 40,188 SD cases (- 48.9%) by 2021. These results were paralleled by a similar decline in notifiable severe cases. However, average duration of hospitalization of the cases remained constant during this period. CONCLUSIONS: Hospital coding of CDI and notification to authorities has approximately halved from 2015 to 2021. Potential influential factors include hospital hygiene campaigns, implementation of antibiotic stewardship programs, social distancing due to the COVID-19 pandemic, and a decrease in more pathogenic subtypes of bacteria. Further research is necessary to validate the multiple possible drivers for this development.

[Consensus paper treatment of acute traveler's diarrhea. Practice recommendation for travel advice]. / Konsensuspapier Therapie der akuten Reisediarrhö : Eine Praxisempfehlung für die Reiseberatung.

BACKGROUND: In times of mass tourism, traveler's diarrhea is one of the most common health problems of long-distance travel. Globally, some 40 million cases occur annually. Travellers to risk areas should therefore be comprehensively advised beforehand, as to what action to take in case of an acute traveler's diarrhea and what drugs to add to their first-aid kit. To date none, or hardly any specific studies or valid specific guidelines for the treatment of traveler's diarrhea are available for Germany. METHOD: Drafting a consensus paper based on results of a specialists' meeting to evaluate therapeutic options in the treatment of acute uncomplicated travelers' diarrhea. The foundation for the present consensus recommendations is current evidence on antidiarrheals available in Germany for symptomatic treatment of gastrointestinal infections, summarized in the S2k guideline for gastrointestinal infections and Whipple's disease. Further taken into account for the present consensus recommendations were Pubmed-listed publications on symptomatic treatment of traveler's diarrhea, practical aspects, and the experts' experience in travel medicine. RESULTS AND CONCLUSION: For the treatment of acute uncomplicated traveler's diarrhea - more than 90 % of all cases - the secretion inhibitor racecadotril is considered first choice, based on our evaluation criteria. The previously usual practice of recommending the antimotility drug loperamide as first choice should be reconsidered, in favor of the recent active ingredient racecadotril. Antibiotics should be used only in complicated cases. A large number of travelers who generally demand antibiotic therapy should be disabused of their expectations. Other therapeutic measures that are currently available for the treatment of acute diarrhea while traveling play a subordinate role.

The societal impact of herpes zoster and postherpetic neuralgia on patients, life partners, and children of patients in Germany.

The aim of this study was to assess the impact of herpes zoster (HZ) and postherpetic neuralgia (PHN) on the daily activities of patients and family members who care for them. Some former patients and family members participated in face-to-face interviews or in a T-group meeting (qualitative phase) and some participated in telephone interviews (quantitative phase). They all expressed feelings of helplessness and frustration mixed with depression, sadness, or rage. Many of the former patients said their lives stopped, in contrast to family members who said that their lives were busy and stressful. Family members caring for patients with PHN were more psychologically stressed than those caring for patients with HZ. Although former patients appreciated the psychological and emotional support given by their family members, they underestimated the impact that their disease had on them. Former patients and their family never forgot this illness and its considerable impact on their lives, particularly when PHN occurred. We need to raise the awareness of the general public about the real life impact of HZ and PHN and their often severe, debilitating consequences and the potential benefits from vaccination.

[Pneumococcal Vaccination Coverage Rates (VCRs) Among Persons with Vaccine-Relevant Underlying Conditions and Persons Aged 60 Years and Older - An Analysis of Secondary Data from the Statutory Health Insurance (SHI) System]. / Impfquoten der Pneumokokken-Impfung bei Personen mit impfrelevanten Grunderkrankungen und Personen ab 60 Jahren ­ Eine Analyse von Sekundärdaten der Gesetzlichen Krankenversicherung (GKV).

BACKGROUND: In addition to standard vaccination for patients aged 60 and older, the Standing Committee on Vaccination (STIKO) recommends immunization against pneumococci for anyone at increased risk, including patients with chronic vaccine-relevant underlying conditions. In Germany, the Robert Koch Institute (RKI) regularly publishes vaccination coverage rates (VCRs) for these patient groups, without stratifying by other parameters. This study examines VCRs of patients with underlying chronic diseases, stratified by disease groups and entities, the re-vaccination rate, and VCRs in patients aged 60 years and older. METHODS: This descriptive retrospective cohort study is based on a sample of about 4 million SHI-insured patients aged 16 years and older for the years 2014 to 2019, from the Institute for Applied Health Research (InGef) database. The sample is representative of age and sex distribution in the German population. RESULTS: Extrapolated to the total SHI-population, the overall pneumococcal VCR in patients aged 60 years and older was 45.9 % (of n= InGef standard vaccination cohort: 1 009 763). Among all at-risk patients aged 16 years and older with chronic underlying diseases, only 17.1 % had received an indicated vaccination (InGef indicated vaccination cohort: 1 379 680). Stratified by disease entity, those with underlying pulmonary emphysema had the highest VCR, at 39.0 % (of n= 28 121). Of those who received a vaccination due to an underlying chronic disease, only 23.9 % were re-vaccinated after 6 years (InGef re-vaccination cohort: 12 328). Across all vaccination cohorts, VCRs increased with age. DISCUSSION: The recommendations made by STIKO for pneumococcal vaccination based on age or an underlying chronic condition are not being implemented adequately in Germany. Although STIKO explicitly recommends vaccination from 60 years of age, the 60 to 64-year-old age group had a strikingly low VCR (13.0 % of n=268 862). Fewer than one in five patients aged 16 years and older with an underlying chronic condition had received the recommended indicated vaccination. To adequately prevent potential disease, higher vaccination rates should be targeted. This could probably be achieved through more stringent vaccination management, appropriate software solutions with vaccination reminders, monetary incentives for achieving higher vaccination rates and documentation of vaccination status in disease management programs.

Epidemiology and Risk Factors of Clostridioides difficile Infections in Germany: A Health Claims Data Analysis.

INTRODUCTION: Clostridioides difficile infection (CDI) is increasingly recognized as a public health threat at the community level in addition to being one of the most common causes of healthcare-associated infections. In Germany, the epidemiology of CDI is primarily informed by national hospital-based CDI surveillance. We used health claims data from Germany to obtain valuable insights on population-level disease burden and risk factors for CDI. METHODS: This was a retrospective cohort study using a representative sample from the InGef research database. Overall and age- and sex-stratified CDI incidence rates were estimated for German adults from 2013 to 2017 using different case definitions (i.e., main, broad, strict), and further stratified by setting (inpatient versus outpatient). Risk factors for CDI were assessed for the 2013-2016 period. RESULTS: The CDI incidence rate was high but declined by 15.3% from 2013 [141 (95% confidence interval, CI 137-145) cases/100,000 person-years] to 2017 [120 (95% CI 116-123)]. Annual CDI incidence rates were higher in female patients and the elderly. The most important risk factors for CDI were chronic inflammatory bowel disease [odds ratio (OR) 4.7, 95% CI 4.0-5.5], chemotherapy (OR 4.7, 95% CI 4.1-5.2), chronic kidney disease (OR 2.9, 95% CI 2.6-3.3), and ciprofloxacin receipt (OR 2.6, 95% CI 2.4-2.8). CONCLUSIONS: Despite prevention strategies leading to declining incidence, CDI remains an important public health threat in Germany, with a high burden in the hospital setting and an outpatient epidemiology that is poorly understood. These findings, which are relevant both regionally and globally, can be used as a basis for further research on the full burden of CDI in Germany.

Epidemiology of Clostridioides difficile Infections in Germany, 2010-2019: A Review from Four Public Databases.

INTRODUCTION: Clostridioides difficile infection (CDI) is a recognized global threat especially for vulnerable populations. It is of particular concern to healthcare providers as it is found in both hospital and community settings, with severe courses, frequent recurrence, high mortality and substantial financial impact on the healthcare system. The CDI burden in Germany has been described and compared by analysing data from four different public databases. METHODS: Data on hospital burden of CDI have been extracted, compared, and discussed from four public databases for the years 2010-2019. Hospital days due to CDI were compared to established vaccine preventable diseases, such as influenza and herpes zoster, and also to CDI hospitalisations in the United States (US). RESULTS: All four databases reported comparable incidences and trends. Beginning in 2010, population-based hospitalised CDI incidence increased to a peak of > 137/100,000 in 2013. Then, incidence declined to 81/100,000 in 2019. Hospitalised patients with CDI were predominantly > 50 years of age. The population-based incidence of severe CDI was between 1.4 and 8.4/100,000 per year. Recurrence rates were between 5.9 to 6.5%. More than 1,000 CDI deaths occurred each year, with a peak of 2,666 deaths in 2015. Cumulative CDI patient days (PD) were between 204,596 and 355,466 each year, which exceeded cumulated PD for influenza and herpes zoster in most years, though year-to-year differences were observed. Finally, hospitalized CDI incidence was higher in Germany than in the US, where the disease is well recognized as a public health threat. CONCLUSIONS: All four public sources documented a decline in CDI cases since 2013, but the disease burden remains substantial and warrants continued attention as a severe public health challenge.

Therapy of uncomplicated falciparum malaria in Europe: MALTHER - a prospective observational multicentre study.

BACKGROUND: Malaria continues to be amongst the most frequent infectious diseases imported to Europe. Whilst European treatment guidelines are based on data from studies carried out in endemic areas, there is a paucity of original prospective treatment data. The objective was to summarize data on treatments to harmonize and optimize treatment for uncomplicated malaria in Europe. METHODS: A prospective observational multicentre study was conducted, assessing tolerance and efficacy of treatment regimens for imported uncomplicated falciparum malaria in adults amongst European centres of tropical and travel medicine. RESULTS: Between December 2003 and 2009, 504 patients were included in 16 centres from five European countries. Eighteen treatment regimens were reported, the top three being atovaquone-proguanil, mefloquine, and artemether-lumefantrine. Treatments significantly differed with respect to the occurrence of treatment changes (p = 0.005) and adverse events (p = 0.001), parasite and fever clearance times (p < 0.001), and hospitalization rates (p = 0.0066) and durations (p = 0.001). Four recrudescences and two progressions to severe disease were observed. Compared to other regimens, quinine alone was associated with more frequent switches to second line treatment, more adverse events and longer inpatient stays. Parasite and fever clearance times were shortest with artemether-mefloquine combination treatment. Vomiting was the most frequent cause of treatment change, occurring in 5.5% of all patients but 9% of the atovaquone-proguanil group. CONCLUSIONS: This study highlights the heterogeneity of standards of care within Europe. A consensus discussion at European level is desirable to foster a standardized management of imported falciparum malaria.

A comparison of coronavirus disease 2019 and seasonal influenza surveillance in five European countries: France, Germany, Italy, Spain and the United Kingdom.

BACKGROUND: In response to the coronavirus disease (COVID-19) outbreak that unfolded across Europe in 2020, the World Health Organisation (WHO) called for repurposing existing influenza surveillance systems to monitor COVID-19. This analysis aimed to compare descriptively the extent to which influenza surveillance systems were adapted and enhanced and how COVID-19 surveillance could ultimately benefit or disrupt routine influenza surveillance. METHODS: We used a previously developed framework in France, Germany, Italy, Spain and the United Kingdom to describe COVID-19 surveillance and its impact on influenza surveillance. The framework divides surveillance systems into seven subsystems and 20 comparable outcomes of interest and uses five evaluation criteria based on WHO guidance. Information on influenza and COVID-19 surveillance systems were collected from publicly available resources shared by European and national public health agencies. RESULTS: Overall, non-medically attended, virological, primary care and mortality surveillance were adapted in most countries to monitor COVID-19, although community, outbreak and hospital surveillance were reinforced in all countries. Data granularity improved, with more detailed demographic and medical information recorded. A shift to systematic notification for cases and deaths enhanced both geographic and population representativeness, although the sampling strategy benefited from the roll out of widespread molecular testing. Data communication was greatly enhanced, contributing to improved public awareness. CONCLUSIONS: Well-established influenza surveillance systems are a key component of pandemic preparedness, and their upgrade allowed European countries to respond to the COVID-19 pandemic. However, uncertainties remain on how both influenza and COVID-19 surveillance can be jointly and durably implemented.

The disease burden of influenza beyond respiratory illness.

Although influenza is primarily considered a respiratory infection and causes significant respiratory mortality, evidence suggests that influenza has an additional burden due to broader consequences of the illness. Some of these broader consequences include cardiovascular events, exacerbations of chronic underlying conditions, increased susceptibility to secondary bacterial infections, functional decline, and poor pregnancy outcomes, all of which may lead to an increased risk for hospitalization and death. Although it is methodologically difficult to measure these impacts, epidemiological and interventional study designs have evolved over recent decades to better take them into account. Recognizing these broader consequences of influenza virus infection is essential to determine the full burden of influenza among different subpopulations and the value of preventive approaches. In this review, we outline the main influenza complications and societal impacts beyond the classical respiratory symptoms of the disease.

The impact of herpes zoster and post-herpetic neuralgia on quality-of-life.

BACKGROUND: The potentially serious nature of herpes zoster (HZ) and the long-term complication post-herpetic neuralgia (PHN) are often underestimated. One in four people will contract herpes zoster in their lifetime, with this risk rising markedly after the age of 50 years, and affecting one in two in elderly individuals. Pain is the predominant symptom in all phases of HZ disease, being reported by up to 90% of patients. In the acute phase, pain is usually moderate or severe, with patients ranking HZ pain as more intense than post-surgical or labour pains. Up to 20% of patients with HZ develop PHN, which is moderate-to-severe chronic pain persisting for months or years after the acute phase. We review the available data on the effect of HZ and PHN on patients' quality-of-life. DISCUSSION: Findings show that HZ, and particularly PHN, have a major impact on patients' lives across all four health domains--physical, psychological, functional and social. There is a clear correlation between increasing severity of pain and greater interference with daily activities. Non-pain complications such as HZ ophthalmicus can increase the risk of permanent physical impairment. Some elderly individuals may experience a permanent loss of independence after an acute episode of HZ. Current challenges in the management of HZ and PHN are highlighted, including the difficulty in administering antiviral agents before pain becomes established and the limited efficacy of pain treatments in many patients. We discuss the clinical rationale for the HZ vaccine and evidence demonstrating that the vaccine reduces the burden of the disease. The Shingles Prevention Study, conducted among >38,000 people aged >or=60 years old, showed that the HZ vaccine significantly reduces the burden of illness and the incidence of both HZ and PHN. In the entire study population, zoster vaccination reduced the severity of interference of HZ and PHN with activities of daily living by two-thirds, as measured by two questionnaires specific to HZ. SUMMARY: A vaccination scheme may positively impact the incidence and course of HZ disease, thereby improving patients' quality-of-life.

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.

Comparison of intramuscular and subcutaneous administration of a herpes zoster live-attenuated vaccine in adults aged ≥50 years: a randomised non-inferiority clinical trial.

Zostavax(®) is a live, attenuated varicella zoster virus (VZV) vaccine developed specifically for the prevention of HZ and PHN in individuals aged ≥50 years. During the clinical development of Zostavax, which was mainly in the US, the vaccine was administrated by the subcutaneous (SC) route. In Europe, many healthcare professionals prefer administering vaccines by the intramuscular (IM) route. This was an open-label, randomised trial conducted in 354 subjects aged ≥50 years. The primary objectives were to demonstrate that IM administration is both non-inferior to SC administration in terms of 4-week post-vaccination geometric mean titres (GMTs), and elicits an acceptable geometric mean fold-rise (GMFR) of antibody titres measured by glycoprotein enzyme-linked immunosorbent assay. Pre-specified non-inferiority was set as the lower bound of the 95% confidence interval (CI) of the GMT ratio (IM/SC) being >0.67. An acceptable GMFR for the IM route was pre-specified as the lower bound of its 95% CI being >1.4. Description of the VZV immune response using the interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay and of the safety were secondary objectives. Participants were randomised to IM or SC administration (1:1). The baseline demographics were comparable between groups; mean age: 62.6 years (range: 50.0-90.5). The primary immunogenicity objectives were met (per protocol analysis): GMT ratio (IM/SC): 1.05 (95% CI: 0.93-1.18); GMFR: 2.7 (2.4-3.0). VZV immune response using IFN-γ ELISPOT were comparable between groups. Frequencies of systemic adverse events were comparable between groups. Injection-site reactions were less frequent with IM than SC route: erythema (15.9% versus 52.5%), pain (25.6% versus 39.5%) and swelling (13.6% versus 37.3%), respectively. In adults aged ≥50 years, IM administration of Zostavax elicited similar immune responses to SC administration and was well tolerated, with fewer injection-site reactions than with SC administration.

Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective.

Herpes zoster (HZ) is primarily a disease of nerve tissue but the acute and longer-term manifestations require multidisciplinary knowledge and involvement in their management. Complications may be dermatological (e.g. secondary bacterial infection), neurological (e.g. long-term pain, segmental paresis, stroke), ophthalmological (e.g. keratitis, iridocyclitis, secondary glaucoma) or visceral (e.g. pneumonia, hepatitis). The age-related increased incidence of HZ and its complications is thought to be a result of the decline in cell-mediated immunity (immunosenescence), higher incidence of comorbidities with age and social-environmental changes. Individuals who are immunocompromised as a result of disease or therapy are also at increased risk, independent of age. HZ and its complications (particularly postherpetic neuralgia) create a significant burden for the patient, carers, healthcare systems and employers. Prevention and treatment of HZ complications remain a therapeutic challenge despite recent advances. This is an overview of the multidisciplinary implications and management of HZ in which the potential contribution of vaccination to reducing the incidence HZ and its complications are also discussed.

Amebic liver abscess--rare need for percutaneous treatment modalities.

BACKGROUND: Given the often unspecific symptoms of amebic liver abscess, an analysis was done to recognize the most common patterns of presentation. Since treatment recommendations are still inconsistent comparing conservative and interventional treatment modalities, we evaluated treatment modalities in our patients. METHODS: A retrospective case series of all patients with confirmed amebic liver abscess was conducted. Age, sex, country of origin or travel, symptoms, and physical and laboratory findings were recorded. Particular attention was given to the need for interventional measures. RESULTS: 62 patients were reviewed, and nearly all of them (95%) had a travel history. The most common findings were fever (97%), abdominal pain (95%), and hepatomegaly (79%). 11% still had no amebic antibodies on presentation but an increase in the follow-up examinations. In 5% needle aspiration was performed to allow differentiation between amebic and pyogenic etiology. Metronidazole alone quickly cleared symptoms in 92% of the patients. In 8% only, there was a therapeutic need for interventional procedures (3% already ruptured, 5% large abscess formation with the danger of rupture). CONCLUSIONS: In travelers with fever, abdominal pain, and hepatomegaly amebic liver abscess must be considered. Medical treatment with metronidazole is effective in more than 90%. Only in very few cases there is a need for invasive therapeutic modalities.

Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the efficacy and safety of a skin-patch vaccine containing the pathogen's heat-labile toxin (LT) in a population of travellers to Mexico and Guatemala. METHODS: In this phase 3, randomised, double-blind, placebo-controlled field trial, healthy adults (aged 18-64 years) travelling from Germany or the UK to Mexico or Guatemala were assigned in a 1:1 ratio by a dynamic electronic randomisation system to receive transcutaneous immunisation with a patch containing 37.5 µg of ETEC LT or a placebo patch. Participants, site staff, and the investigators who did the analyses were masked to group assignment. Participants were vaccinated before travel, with two patches given 14 days apart. In the destination country, participants tracked stool output in a diary and provided stool samples for pathogen identification if diarrhoea occurred. The primary endpoint was the proportion of participants with at least one episode of moderate-to-severe diarrhoea (defined as four or more unformed stools in a 24 h period) in which either or both ETEC enterotoxins (LT and heat-stable toxin [ST]) were detected. The study is registered at ClinicalTrials.gov, number NCT00993681. FINDINGS: 2036 participants were recruited and randomly assigned between Oct 14, 2009, and Aug 13, 2010, with 1016 allocated to receive the LT patch and 1020 the placebo patch. 821 participants in the LT-patch group and 823 in the placebo group received both vaccinations and were analysed in the per-protocol population. 30 (3.7%, 95% CI 2.5-5.2) participants in the LT-patch group and 46 (5.6%, 4.1-7.4) in the placebo group had moderate or severe ETEC diarrhoea (vaccine efficacy 34.6%, -2.2 to 58.9; p=0.0621). 9333 local (ie, patch-site) adverse events (including erythema, rash, pruritus, hyperpigmentation, pain, hypopigmentation, and oedema) occurred in 943 (93%) of 1015 participants in the LT-patch group, compared with 1444 local adverse events in 574 (56%) of 1019 participants in the placebo group (p<0.0001). Serious adverse events occurred in 25 participants (14 in the LT-patch group and 11 in the placebo group), with all regarded as either unrelated or possibly related to treatment. Vaccine-induced hyperpigmentation persisted for at least 180 days after vaccination in 150 (18%) of the 849 participants who received both vaccinations and returned for final assessment in the LT-patch group, compared with none of the 842 participants in the placebo group. The vaccine was immunogenic, with a post-vaccination geometric mean titre of LT-specific serum immunoglobulin G of 3400.29, compared with 315.41 in the placebo group. INTERPRETATION: Although the LT antigen was delivered effectively by the skin patch, the vaccine did not protect travellers against diarrhoea caused by ETEC or other organisms. Future vaccines against travellers' diarrhoea might need to include several antigens against various diarrhoeal pathogens, and might need to be able to generate mucosal and higher systemic immunity.

Impact of herpes zoster and post-herpetic neuralgia on patients' quality of life: a patient-reported outcomes survey.

BACKGROUND: The impact of herpes zoster (HZ) and post-herpetic neuralgia (PHN) on patients' quality of life (QoL) is currently poorly documented. SUBJECTS AND METHODS: Telephone interviews in Germany identified patients ≥50 years old with painful HZ diagnosed during the previous 5 years. Bespoke questions evaluated previous HZ episodes. RESULTS: Of 11,009 respondents, 280 met the screening criteria, and 32 (11%) developed PHN. PHN was associated with significantly worse outcomes than HZ (all P < 0.05). Mean pain scores associated with PHN and HZ, respectively, were 7.1 and 6.2 (average) and 8.2 and 7.0 (worst). Many patients with PHN (91%) and HZ (73%) experienced problems with daily activities, including work, studies, housework, family and leisure activities. Mean pain interference scores in patients with PHN versus HZ were highest for sleep (6.5 versus 4.9), normal work (6.1 versus 4.4) and mood (5.9 versus 4.4). Most employed interviewees with PHN (70%) and HZ (64%) stopped work during the disease. Pain and QoL outcomes were not significantly different between all patients versus those diagnosed during the previous 12 months or between patients aged 50-59 years versus ≥60 years. CONCLUSIONS: HZ causes substantial pain, which seriously interferes with many aspects of daily life, particularly in patients with PHN.