The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE).

This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.

Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE).

Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs' knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.

Emergency Surgery in Acute Diverticulitis: A Systematic Review.

BACKGROUND: Acute diverticulitis is a common disease with public health significance. Many studies with a high level of evidence have been published recently on the surgical management of acute diverticulitis. OBJECTIVE: The aim of this systematic review was to define the accurate surgical management of acute diverticulitis. DATA SOURCES: Medline, Embase, and the Cochrane Library were sources used. STUDY SELECTION: One reviewer conducted a systematic study with combinations of key words for the disease and the surgical procedure. Additional studies were searched in the reference lists of all included articles. The results of the systematic review were submitted to a working group composed of 13 practitioners. All of the conclusions were obtained by full consensus and validated by an external committee. INTERVENTIONS: The interventions assessed were laparoscopic peritoneal lavage, primary resection with anastomosis with or without ileostomy, and the Hartmann procedure, with either a laparoscopic or an open approach. MAIN OUTCOME MEASURES: Morbidity, mortality, long-term stoma rates, and quality of life were measured. RESULTS: Seventy-one articles were included. Five guidelines were retrieved, along with 4 meta-analyses, 14 systematic reviews, and 5 randomized controlled trials that generated 8 publications, all with a low risk of bias, except for blinding. Laparoscopic peritoneal lavage showed concerning results of deep abscesses and unplanned reoperations. Studies on Hinchey III/IV diverticulitis showed similar morbidity and mortality. A reduced length of stay with Hartmann procedure compared with primary resection with anastomosis was reported in the short term, and in the long term, more definite stoma along with poorer quality of life was reported with Hartmann procedure. No high-quality data were found to support the laparoscopic approach. LIMITATIONS: Trials specifically assessing Hinchey IV diverticulitis have not yet been completed. CONCLUSIONS: High-quality studies showed that laparoscopic peritoneal lavage was associated with an increased morbidity and that Hartmann procedure was associated with poorer long-term outcomes than primary resection with anastomosis with ileostomy, but Hartmann procedure is still acceptable, especially in high-risk patients.

A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic Working Group of the European Network on ME/CFS (EUROMENE).

Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs' knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.

Helicobacter pylori infection and extragastric diseases in 2017.

The huge variety of extragastric diseases linked to Helicobacter pylori infection is widely known, and new studies are conducted every year on this topic. Neurological disorders and metabolic syndrome are some of the main issues debated in the most recent literature. Articles on the association of H. pylori with skin diseases, inflammatory bowel diseases, immunologic impairment, kidney dysfunction, allergic asthma, and respiratory diseases have been published as well. In this perspective, eradication therapy for this infection could become a mandatory measure in prevention strategy.

[Epidemiology of Helicobacter pylori infection and gastric cancer]. / Epidémiologie de l'infection à Helicobacter pylori et du cancer gastrique.

The incidence of H. pylori infection is steadily declining in developed countries, with a prevalence reduced in younger patients (less than 20 % but remaining still high (over 50 %) in the elderly population. The incidence is stable in developing countries, with a prevalence of 70-80%. Adenocarcinoma is the main type of gastric malignancy. The mechanisms of carcinogenesis and risk factors differ depending on the location proximal (cardia) or distal and the histological type "intestinal" or "diffuse". With approximately 6500 new cases per year and a 80% mortality in France, gastric cancer is relatively frequent and severe. The current dominant etiologic role of H. pylori infection explains the epidemiological changes of recent decades: the decline due to reduced incidence of distal cancers of "intestinal" type whereas "diffuse" and proximal cancer are increasing, the average age of onset of 70 years with a male preponderance associated with the high prevalence of distal intestinal type. The cardia cancer occurs earlier and has a worst prognosis. The main risk factors are chronic gastritis induced by H. pylori, smoking, salty and smoked food, a family history of gastric cancer, Lynch syndrome and hereditary diffuse gastric cancer.

Comparative evaluation of 29 commercial Helicobacter pylori serological kits.

BACKGROUND: Serology is a noninvasive diagnostic method for the detection of Helicobacter pylori infection. Many commercial kits are now on the market. It is necessary to assess their performances to help the user to choose the most appropriate. MATERIAL AND METHODS: The performances of 29 commercial serological tests detecting antibodies to Helicobacter pylori (17 enzyme-linked immunosorbent assay and 12 near-patient tests) were evaluated using sera from 108 patients prospectively selected from gastroenterology departments of five French hospital centers. These patients were infected (45) or uninfected (47) by H. pylori, or had doubtful results (16), according to the gold standard (culture or histology plus rapid urease test or urea breath test). The tests were evaluated by determining the usual parameters of performance: sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Two analyzes were performed including or not the 16 patients with doubtful infection as uninfected or not analyzed. RESULTS: Depending on the type of analysis, four or two of the 17 enzyme-linked immunosorbent assay tests presented excellent results with the five performance parameters >90%. Calculation of the Youden index allowed to show significantly better performances for one of the 4. Performances of the 12 near-patient tests were lower with accuracies <90% for all except one test. CONCLUSION: These data should help the users to choose the kit the most appropriate to their goals.

Separating Patients with SEID from Those with CFS in the French ME/CFS Association, with Some Thoughts on Nomenclature.

In 2015, the American Institute of Medicine, now called the National Academy of Medicine, (IOM/NAM) proposed new diagnostic criteria for both Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and a new label: Systemic Exertion Intolerance Disease (SEID). This study aimed to evaluate the SEID criteria among members of the French Association of ME/CFS (ASFC) and their opinion about this new name. We sent an anonymous questionnaire to 494 ASFC members, using French-translated questions derived from the IOM/NAM tool kit. Among the 178/231 responding subjects who reported ME/CFS diagnosis, 150 (84%) met the criteria of SEID. For each set of questions, we identified some of them that significantly distinguished SEID from non-SEID patients concerning unrefreshing sleep, cognitive disorders, and orthostatic intolerance items. Forty-six percent of the respondents considered the "SEID" terminology as more appropriate than "CFS", 39% considered it inappropriate, and 15% had no opinion. Some questions better identified the SEID criteria. The IOM/NAM SEID criteria captured a large part of ASFC members suffering from ME/CFS. However, this new SEID label was not well accepted by the subjects, nor were the other denominations, suggesting that a better term should be found. Pending development of specific markers, further work with patient communities is needed to find a more suitable label.

Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease.

INTRODUCTION: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. Patients often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk is the development of lymphoma in some cases. To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry. MATERIAL AND METHODS: An anonymous questionnaire following the recommendations of the Institute of Medicine/National Academy of Medicine for screening of the new SEID criteria was created in French and mailed to 50 patients. RESULTS: Thirty-nine (78%) contacted patients responded. The studied population was mainly constituted of women (90%) with an average age of 50 (18-59) years. Smoking was a constant factor in all patients. A total of 28/39 (72%) respondents met the SEID symptoms criteria. Severe chronic fatigue for more than 6 months was noted in 36/39 cases (92%). Unrefreshing sleep, post-exertional malaise, cognitive impairment, and orthostatic intolerance were described in 30/39 (77%), 32/39 (82%), 28/39 (72%), and 27/39 (69%) cases, respectively. Pain (arthralgia, myalgia, headache) was present in 26/39 (67%) cases. The most prominent SEID symptoms were fatigue, followed by post-exercise discomfort and cognitive difficulties. The most disabling symptom was non-restorative sleep, followed by pain. An inflammatory and/or autoimmune context was noted in 13 patients (33%), and these comorbidities could have favored the deterioration of the general condition. Three patients also presented with fibromyalgia. However, 3 patients did not mention any complaints. CONCLUSION: This survey indicated that patients with PPBL most often initially presented with disabling chronic fatigue, chronic pain, and other symptoms suggestive of SEID but requiring more studies to confirm it. Education of medical staff about the symptoms of PPBL should be encouraged to better assess this peculiar condition.

The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE).

We have developed a Europe-wide approach to investigating the economic impact of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), facilitating acquisition of information on the economic burden of ME/CFS, and international comparisons of economic costs between countries. The economic burden of ME/CFS in Europe appears large, with productivity losses most significant, giving scope for substantial savings through effective prevention and treatment. However, economic studies of ME/CFS, including cost-of-illness analyses and economic evaluations of interventions, are problematic due to different, arbitrary case definitions, and unwillingness of doctors to diagnose it. We therefore lack accurate incidence and prevalence data, with no obvious way to estimate costs incurred by undiagnosed patients. Other problems include, as for other conditions, difficulties estimating direct and indirect costs incurred by healthcare systems, patients and families, and heterogeneous healthcare systems and patterns of economic development across countries. We have made recommendations, including use of the Fukuda (CDC-1994) case definition and Canadian Consensus Criteria (CCC), a pan-European common symptom checklist, and implementation of prevalence-based cost-of-illness studies in different countries using an agreed data list. We recommend using purchasing power parities (PPP) to facilitate international comparisons, and EuroQol-5D as a generic measure of health status and multi-attribute utility instrument to inform future economic evaluations in ME/CFS.

[Hereditary and acquired iron overload]. / Les surcharges en fer.

Since the discovery of HFE gene in 1996, considerable progress has been made concerning the iron-metabolism and its major abnormalities. Five types of hereditary hemochromatosis are actually known: type 1 (HFE gene), type 2A (HJV gene), type 2B (HAMP gene), type 3 (TfR2 gene), type 4 (SLC40A1 gene). The HFE C282Y +/+ mutation is responsible for the most frequent type of hemochromatosis in France. Various secondary causes can lead to iron-overload: associated genetic diseases, exogenous iron intake, thalassaemia and refractory anaemia, hepatic siderosis, alcoholic hepatitis, cutaneous porphyria and cirrhosis. The deleterious consequences of iron-overload are due to the interactions of the environmental factors. The role of HFE heterozygote mutations is still discussed. In clinical practice, the interpretation of a serum ferritin increase is a frequent problem that needs a careful evaluation based on the tranferrin saturation measurement. Significant increase of both these factors is in favour of an HFE C282Y +/+ hemochromatosis, after exclusion of a hepatocellular insufficiency or a refractory anaemia. Nevertheless, high ferritin is not always a marker of iron-overload. Thus, there are many disorders increasing the serum ferritin levels without iron overload : cytolysis (hepatic...), inflammatory or infectious syndromes, high alcohol intake, neoplasia... Looking for HFE mutations help to separate type 1 hemochromatosis from other conditions mainly hepatic siderosis (metabolic disorders). The identification of rare types of hemochromatosis (types 2-4) is only required in particular cases. The evaluation of the iron overload is now based on hepatic MRI determination rather than liver biopsy. Repeated phlebotomies remain the essential way to decrease the iron overload in HFE hemochromatosis and to prevent the occurrence of severe and irreversible complications (cirrhosis, arthropathies, cardiac failure, and diabetes). Because of the link established between the amount of iron-overload and the occurrence of complications and the mortality over-risk in HFE C282Y +/+ hemochromatosis, venesections must be started when serum ferritin is higher than 300 microg/l in man and 200 microg/l in woman, whatever the clinical manifestations are and obviously before the symptomatic phase of the disease.

[Advantages and limitations of diagnostic methods for H. pylori infection]. / Avantages et inconvénients des différentes méthodes diagnostiques de l'infection à H. pylori.

The diagnosis of H. pylori infection is based on methods requiring gastric biopsies performed during endoscopy (histology, culture, rapid urease test, PCR) or on non-invasive methods (serology, 13C urea breath test, stool antigen test). Histology is routinely performed on gastric biopsies, also allowing the description and the classification of the gastric inflammatory mucosal lesions associated with H. pylori. The rapid urease test is less sensitive but specific. It can be done by the gastroenterologist himself, mainly when a duodenal ulcer is found at endoscopy,and may be followed by histological testing in case of a negative result. The culture of biopsies may be helpful in determining in vitro patterns of antimicrobial resistance and sensitivity in planning second line treatment for a patient after eradication failure. Non-invasive methods are not appropriate for determining the underlying disease, which may be associated with H. pylori infection. Serological tests are widely available and cheap, and may be helpful-in screening populations or in confirming the presence H. pylori infection in case of equivocal results of the other diagnostic methods due to bleeding ulcers, antibiotic and/or antisecretory treatments. The 13C urea breath test is the most accurate method in patients irrespective of age. Stool antigen testing is a promising method because its diagnostic performances approach those obtained with urea breath test. This technique is easy to perform, and its accuracy may be improved by the use of monoclonal antibodies recently proposed for capturing H. pylori antigen in stool specimen. The eradication control is recommended at least 4 weeks after the end of the eradication treatment or at least 2 weeks after antisecretory treatment to obtain high sensitive results. If endoscopic control is necessary, a biopsy culture with antibiotic testing is recommended in combination with histology, because of the actual development of antibiotic resistances. Looking for H. pylori virulence markers remains a promising research topic but is not yet recommended in routine practice.

[New-generation proton pump inhibitors: progress in the treatment of peptic acid diseases?]. / Les nouveaux inhibiteurs de la pompe à protons, un progrès dans la prise en charge des maladies acido-peptiques?

EFFECTS AND INCONVENIENCIES OF THE OLDER PRODUCTS: The proton pump inhibitors (PPIs) are now universally considered the treatment of choice for management of gastric-acid-related diseases, mainly gastro-oesophageal reflux disease (GERD). These drugs share similar properties: general structure, acid-activation step, covalent binding to the proton pump of the gastric parietal cell via the production of covalent disulphide bonds, relatively stable inhibition of H+,K+-ATPase. However, the older PPIs (omeprazole, lansoprazole et pantoprazole) have notable limitations. These drugs exhibit substantial interpatient variability and may have significant interactions with other drugs. These first-generation PPIs also do not achieve a rapid and sustained suppression of gastric acid, leading to the development of new acid-pump antagonists. The new-generation PPIs, esomeprazole and rabeprazole, offer several pharmacokinetic advantages: lower oxidative hepatic metabolism rate via the CYP 2C19 reducing the activity variations due to genetic polymorphisms and decreasing the risk of significant drug-drug interactions (advantages mainly for rabeprazole), lower metabolic clearance of esomeprazole (S-enantiomer of omeprazole) increasing plasma concentrations and acid suppression of this new PPI, higher accumulation of rabeprazole in the parietal cell due to its higher pKa. Gastric pH studies and therapeutic trials have demonstrated significant advantages of esomeprazole and rabeprazole compared with the older PPIs, which omeprazole is the prototype: a greater inhibition of acid secretion, a more rapid onset of action to provide reflux symptoms relief over 24 hours with lower GERD-related cost for rabeprazole, a sustained acid suppression, cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole, reduced potential for clinically significant drug-drug interactions with rabeprazole compared with omeprazole and esomeprazole. Due to their properties, esomeprazole and rabeprazole are the best candidates for "on demand" treatment of GERD.

Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: a French multicenter study.

The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5years (range: 1.6-35). Two patients developed Waldenström's macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.

[New recommendations for the diagnosis and the treatment of Helicobacter pylori infection]. / Nouvelles recommandations pour le diagnostic et le traitement de l'infection àHelicobacter pylori.

Management of Helicobacter pylori infection is evolving. New data concern the role of the bacterium in various clinical conditions, the indications of H. pylori testing, diagnosis procedures and eradication treatment regimens. H. pylori should be sought and eradicated before starting NSAIDs treatment, in aspirin users with a history of gastroduodenal ulcer, and in patients presenting with chronic dyspepsia, high risk factors of gastric cancer, unexplained iron deficiency anaemia, vitamin B12 deficiency, or immune (idiopathic) thrombocytopenic purpura. The Urea Breath Test remains the best test to diagnose H. pylori infection, whereas serology is the only test, which is not affected by local changes in the stomach. Molecular tests can be used to detect H. pylori and clarithromycin and/or fluoroquinolone resistance in gastric biopsies without necessitating culture. In regions of high clarithromycin resistance, such as France, sequential treatment or bismuth-containing quadruple therapies are replacing standard triple therapies for the first-line empirical treatment.