Antoine Flahault

Estimating the impact of school closure on influenza transmission from Sentinel data

The threat posed by the highly pathogenic H5N1 influenza virus requires public health authorities to prepare for a human pandemic. Although pre-pandemic vaccines and antiviral drugs might significantly reduce illness rates, their stockpiling is too expensive to be practical for many countries. Consequently, alternative control strategies, based on non-pharmaceutical interventions, are a potentially attractive policy option. School closure is the measure most often considered. The high social and economic costs of closing schools for months make it an expensive and therefore controversial policy, and the current absence of quantitative data on the role of schools during influenza epidemics means there is little consensus on the probable effectiveness of school closure in reducing the impact of a pandemic. Here, from the joint analysis of surveillance data and holiday timing in France, we quantify the role of schools in influenza epidemics and predict the effect of school closure during a pandemic. We show that holidays lead to a 20–29% reduction in the rate at which influenza is transmitted to children, but that they have no detectable effect on the contact patterns of adults. Holidays prevent 16–18% of seasonal influenza cases (18–21% in children). By extrapolation, we find that prolonged school closure during a pandemic might reduce the cumulative number of cases by 13–17% (18–23% in children) and peak attack rates by up to 39–45% (47–52% in children). The impact of school closure would be reduced if it proved difficult to maintain low contact rates among children for a prolonged period.

Chikungunya Fever: A Clinical and Virological Investigation of Outpatients on Reunion Island, South-West Indian Ocean

Background Chikungunya virus (CHIKV) is responsible for acute febrile polyarthralgia and, in a proportion of cases, severe complications including chronic arthritis. CHIKV has spread recently in East Africa, South-West Indian Ocean, South-Asia and autochthonous cases have been reported in Europe. Although almost all patients are outpatients, medical investigations mainly focused on hospitalised patients. Methodology/Principal Findings Here, we detail clinico-biological characteristics of Chikungunya (CHIK) outpatients in Reunion Island (2006). 76 outpatients with febrile arthralgia diagnosed within less than 48 hours were included by general practitioners during the CuraChik clinical trial. CHIK was confirmed in 54 patients and excluded in 22. A detailed clinical and biological follow-up was organised, that included analysis of viral intrahost diversity and telephone survey until day 300. The evolution of acute CHIK included 2 stages: the ‘viral stage’ (day 1–day 4) was associated with rapid decrease of viraemia and improvement of clinical presentation; the ‘convalescent stage’ (day 5–day 14) was associated with no detectable viraemia but a slower clinical improvement. Women and elderly had a significantly higher number of arthralgia at inclusion and at day 300. Based on the study clinico-biological dataset, scores for CHIK diagnosis in patients with recent febrile acute polyarthralgia were elaborated using arthralgia on hands and wrists, a minor or absent myalgia and the presence of lymphopenia (<1G/L) as major orientation criteria. Finally, we observed that CHIKV intra-host genetic diversity increased over time and that a higher viral amino-acid complexity at the acute stage was associated with increased number of arthralgia and intensity of sequelae at day 300. Conclusions/Significance This study provided a detailed picture of clinico-biological CHIK evolution at the acute phase of the disease, allowed the elaboration of scores to assist CHIK diagnosis and investigated for the first time the impact of viral intra-host genetic diversity on the disease course.

Severe Perturbations of the Blood T Cell Repertoire in Polymyositis, But Not Dermatomyositis Patients

Polymyositis and dermatomyositis are diseases characterized by muscle weakness and muscle inflammatory infiltrates. Their pathogenesis remains unclear. A central role for endomysial autoaggressive CD8+ T cells is suspected in polymyositis and for perivascular B cells in dermatomyositis. We compared the T cell repertoire of 10 polymyositis and 10 dermatomyositis patients by immunoscope, a method providing a global assessment of the T cell repertoire and a sensitive detection of clonal T cell expansions. Samples were analyzed qualitatively and quantitatively in the blood (unsorted cells and CD4+ and CD8+ cells) and in muscle infiltrates. Dramatic perturbations of the T cell repertoire were observed in the blood of polymyositis but not dermatomyositis patients (p < 0.0005), the latter being undistinguishable from controls. These perturbations were due to oligoclonal expansions of CD8+ T cells and most blood clonal expansions were also found in muscle. These results indicate that the pathogenesis of polymyositis and dermatomyositis is different and reinforce the view that polymyositis but not dermatomyositis is an autoimmune CD8+ T cell-mediated disease. Moreover, this method may be helpful for the differential diagnosis of polymyositis and dermatomyositis and for noninvasive follow-up of polymyositis patients.

Impact of Chikungunya Virus Infection on Health Status and Quality of Life: A Retrospective Cohort Study

Background Persistent symptoms, mainly joint and muscular pain and depression, have been reported several months after Chikungunya virus (CHIKV) infection. Their frequency and their impact on quality of life have not been compared with those of an unexposed population. In the present study, we aimed to describe the frequency of prolonged clinical manifestations of CHIKV infection and to measure the impact on quality of life and health care consumption in comparison with that of an unexposed population, more than one year after infection. Methodology/Principal Findings In a retrospective cohort study, 199 subjects who had serologically confirmed CHIKV infection (CHIK+) were compared with 199 sero-negative subjects (CHIK–) matched for age, gender and area of residence in La Réunion Island. Following an average time of 17 months from the acute phase of infection, participants were interviewed by telephone about current symptoms, medical consumption during the last 12 months and quality of life assessed by the 12-items Short-Form Health Survey (SF-12) scale. At the time of study, 112 (56%) CHIK+ persons reported they were fully recovered. CHIK+ complained more frequently than CHIK– of arthralgia (relative risk = 1.9; 95% confidence interval: 1.6–2.2), myalgia (1.9; 1.5–2.3), fatigue (2.3; 1.8–3), depression (2.5; 1.5–4.1) and hair loss (3.8; 1.9–7.6). There was no significant difference between CHIK+ and CHIK– subjects regarding medical consumption in the past year. The mean (SD) score of the SF-12 Physical Component Summary was 46.4 (10.8) in CHIK+ versus 49.1 (9.3) in CHIK– (p = 0.04). There was no significant difference between the two groups for the Mental Component Summary. Conclusions/Significance More than one year following the acute phase of infection, CHIK+ subjects reported more disabilities than those who were CHIK–. These persistent disabilities, however, have no significant influence on medical consumption, and the impact on quality of life is moderate.

The Chikungunya Epidemic on La Réunion Island in 2005–2006: A Cost-of-Illness Study

Background This study was conducted to assess the impact of chikungunya on health costs during the epidemic that occurred on La Réunion in 2005–2006. Methodology/Principal Findings From data collected from health agencies, the additional costs incurred by chikungunya in terms of consultations, drug consumption and absence from work were determined by a comparison with the expected costs outside the epidemic period. The cost of hospitalization was estimated from data provided by the national hospitalization database for short-term care by considering all hospital stays in which the ICD-10 code A92.0 appeared. A cost-of-illness study was conducted from the perspective of the third-party payer. Direct medical costs per outpatient and inpatient case were evaluated. The costs were estimated in Euros at 2006 values. Additional reimbursements for consultations with general practitioners and drugs were estimated as €12.4 million (range: €7.7 million–€17.1 million) and €5 million (€1.9 million–€8.1 million), respectively, while the cost of hospitalization for chikungunya was estimated to be €8.5 million (€5.8 million–€8.7 million). Productivity costs were estimated as €17.4 million (€6 million–€28.9 million). The medical cost of the chikungunya epidemic was estimated as €43.9 million, 60% due to direct medical costs and 40% to indirect costs (€26.5 million and €17.4 million, respectively). The direct medical cost was assessed as €90 for each outpatient and €2,000 for each inpatient. Conclusions/Significance The medical management of chikungunya during the epidemic on La Réunion Island was associated with an important economic burden. The estimated cost of the reported disease can be used to evaluate the cost/efficacy and cost/benefit ratios for prevention and control programmes of emerging arboviruses.

Role of videoendoscopy in assessment of pharyngeal function in oropharyngeal dysphagia: Comparison with videofluoroscopy and manometry

Objective: The purpose of the current report is to evaluate the ability of videoendoscopic swallowing study in assessing pharyngeal propulsion and aspiration episodes when compared with videofluoroscopy and manometry. Study Design: Prospective study. Methods: Thirty‐four patients with oropharyngeal dysphagia underwent videoendoscopy of swallowing to assess pharyngeal propulsion as pathologic or non‐pathologic, and aspiration. These features were compared with those found on manometry and videofluoroscopy, which were considered as the reference examinations. Sensitivity, specificity, and positive and negative predictive values of videoendoscopy were estimated, with their 95% confidence intervals. Results: A total agreement between videoendoscopy and videofluoroscopy was found in 76.4% of cases for pharyngeal propulsion and in 82.3% for aspiration. This rate for pharyngeal propulsion reached 82.3% between videoendoscopy and manometry. Moreover, in 24 cases (70.5%) in which videofluoroscopy and manometry agreed for pharyngeal propulsion, 22 were assessed similarly through fiberoscopy. When using fluoroscopy and manometry as reference examinations, videoendoscopy detected nearly 90% (95% confidence interval [CI] = 0.80, 1.0) of impaired pharyngeal propulsion. Concerning aspiration, 70% (95% CI = 0.54, 0.85) of events detected by videoendoscopy were also observed on videofluoroscopy. Sensitivity, specificity, and positive and negative predictive values of videoendoscopy reached a higher rate (90% to 92.8%) when agreement was found between fluoroscopy and manometry. Conclusions: Videoendoscopy is an examination that can be used to detect inexpensively pharyngeal propulsion disorders and aspiration episodes. Laryngoscope, 108:1712–1716, 1998

Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion

Ischemia triggers an inflammatory response that precipitates cell death during reperfusion. Several studies have shown that tissues are protected by ischemic preconditioning (IP) consisting of 10 min of ischemia followed by 10 min of reperfusion just before ischemia. The molecular basis of this protective effect is poorly understood. We used cDNA arrays (20K) to compare global gene expression in liver biopsies from living human liver donors who underwent IP (n=7) or not (n=7) just before liver devascularization. Microarray data were analyzed using paired t test with a type I error rate fixed at α = 2.5 106 (Bonferroni correction). We found that 60 genes were differentially expressed (36 over‐ and 24 underexpressed in preconditioning group). After IP, the most significantly overexpressed gene was IL‐1Ra. This was confirmed by immunoblotting. Differentially expressed were genes involved in apoptosis (NOD2, ephrin‐A1, and calpain) and in the carbohydrate metabolism. A significant increase in the amount of the anti‐apoptotic protein Bcl‐2 in preconditioned livers but no change in the cleavage of procaspase‐3, ‐8, and ‐9 was observed. We also observed an increase in the amount in the inducible nitric oxide synthase. Therefore, the benefits of IP may be associated with the overproduction of IL‐1Ra, Bcl‐2, and NO countering the proinflammatory and proapoptotic effects generated during ischemia‐reperfusion. AlainBarrier NataliaOlaya FranckChiappini FrançoisRoser OlivierScatton CédricArtus BrigitteFranc SandrineDudoit AntoineFlahault BrigitteDebuire DanielAzoulay AntoinetteLemoine Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL‐1Ra, iNOS, and Bcl‐2 in a human model of liver ischemia‐reperfusion. FASEB J. 19, 1617–1626 (2005)

Genetic and environmental risk factors for oral anticoagulant overdose

BackgroundCytochrome P450 2C9 (CYP2C9) allelic variant carriers have been shown to experience hyper-responsiveness to small doses of oral anticoagulants (OAs) (warfarin or acenocoumarol) and a higher bleeding rate.ObjectivesTo determine the relative frequencies of different risk factors for OA overdose including diet, concomitant diseases, drug interactions, recent increment of OA dose and CYP2C9 genetic polymorphism among hospitalised patients.Materials and methodsFrequencies of the different risk factors for OA overdose were determined in a prospective case-control study. Seventy-five consecutive patients with an International normalised ratio (INR) greater than 4 were matched with seventy-five control patients with an INR greater than 2 but less than 3.5 with respect to age, prescribed OA and daily dose. Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was detected by the TaqMan allelic discrimination assay.ResultsDrug interactions and a recent increment of OA dose were the only significant independent risk factors identified in the first analysis with odds ratio 2.13 (95% CI: 1.06–4.28) and 3.38 (95%CI: 1.51–7.57), respectively. A recent increment of OA dose was the only significant independent risk factor identified among the patients treated with coumarin derivatives (acenocoumarol or warfarin), excluding those treated with fluindione; the odds ratio was 4.3 (95% CI: 1.5–12.3). CYP2C9 genetic polymorphism did not significantly predict the increased risk of OA overanticoagulation in this study. However three homozygous CYP2C9*3/CYP2C9*3 genotype patients were found among the cases, whereas no such patients could be identified among controls.ConclusionThis is the first observational study investigating the role of CYP2C9 genetic polymorphism together with other environmental OA overdose risk factors. Our results support the view that although the CYP2C9*3/CYP2C9*3 genotype is associated soon after the introduction of OA with dramatic overanticoagulation, OA overdose is mostly related to environmental factors.

Prévalence et prise en charge de l'insuffisance cardiaque en France : enquête nationale auprès des médecins généralistes du réseau Sentinelles

BACKGROUND Epidemiological data on heart failures epidemiology in France are scarce and mostly hospital based. The present studys objective is to estimate the prevalence of heart failure (HF) and its management, in subjects aged 60 years and older seen by the French general practitioners (GP). METHODS A standardised questionnaire was mailed to 900 GPs of the Sentinelles network, requiring answers for any patient aged 60 years and more, seen on a randomly assigned single day of year 2002. National census and health insurance data were used to estimate prevalence. RESULTS 434 GPs answered, reporting data for 1797 patients aged 60 years and more. The 214 patients with HF, aged 79 years on average, had been seen by a cardiologist in 95% of cases. Results of an echocardiography was available for 58% of HF patients. Compared to non-HF patients, patients with HF were significantly more dependent, more frequently requiring home visit of the GP and more frequently hospitalised (p < 0.001, age adjusted). All the 42% HF patients with a reported left ventricle ejection fraction lower than 40% were treated with an angiotensin converting enzyme inhibitor or an angiotensin receptor inhibitor. The prevalence of HF among patients aged 60 years and older was estimated at 11.9% in general practice (95% confidence interval: 10.5-13.5), and at 2.19% (1.9-2.5) in the general population. The prevalence increased with age, over 20% in persons aged 80 years and more. CONCLUSION HF in patients aged 60 years and more seen in general practice in France is characterised by a high prevalence and medical consumption in terms of required number of hospitalisation and GPs home visit. For the GP, the diagnosis of HF relies on the cardiologist more than on an echocardiography. The therapeutic management seems to fit the actual recommendations.

Mycobacterium ulcerans Ecological Dynamics and Its Association with Freshwater Ecosystems and Aquatic Communities: Results from a 12-Month Environmental Survey in Cameroon

Background Mycobacterium ulcerans (MU) is the agent responsible for Buruli Ulcer (BU), an emerging skin disease with dramatic socioeconomic and health outcomes, especially in rural settings. BU emergence and distribution is linked to aquatic ecosystems in tropical and subtropical countries, especially to swampy and flooded areas. Aquatic animal organisms are likely to play a role either as host reservoirs or vectors of the bacilli. However, information on MU ecological dynamics, both in space and time, is dramatically lacking. As a result, the ecology of the disease agent, and consequently its mode of transmission, remains largely unknown, which jeopardizes public health attempts for its control. The objective of this study was to gain insight on MU environmental distribution and colonization of aquatic organisms through time. Methodology/Principal Findings Longitudinal sampling of 32 communities of aquatic macro-invertebrates and vertebrates was conducted from different environments in two BU endemic regions in Cameroon during 12 months. As a result, 238,496 individuals were classified and MU presence was assessed by qPCR in 3,084 sample-pools containing these aquatic organisms. Our study showed a broad distribution of MU in all ecosystems and taxonomic groups, with important regional differences in its occurrence. Colonization dynamics fluctuated along the year, with the highest peaks in August and October. The large variations observed in the colonization dynamics of different taxonomic groups and aquatic ecosystems suggest that the trends shown here are the result of complex ecological processes that need further investigation. Conclusion/Perspectives This is the largest field study on MU ecology to date, providing the first detailed description of its spatio-temporal dynamics in different aquatic ecosystems within BU endemic regions. We argue that coupling this data with fine-scale epidemiological data through statistical and mathematical models will provide a major step forward in the understanding of MU ecology and mode of transmission.