Fabrice Simon

Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases.

A large chikungunya virus (CHIKV) outbreak emerged in 2005-2006 in the Indian Ocean islands, including Comoros, Mayotte, Mauritius, the Seychelles, and particularly in Reunion Island where 35% of 770,000 inhabitants were infected in 6 months. More recently, circulation of the virus has been documented in Madagascar and in India where CHIKV is spreading rapidly. CHIKV-infected visitors have returned home to nonendemic regions from these islands. We conducted a 14-month prospective observational study on the clinical aspects of CHIKV infection imported to Marseilles, France, in travelers returning from the Indian Ocean islands. A total of 47 patients have been diagnosed with imported CHIKV infection confirmed by serology, reverse transcription-polymerase chain reaction, and/or viral culture. At the early stage of the disease (within 10 days of the disease onset), fever was present in 45 of 47 patients. A rash was present in the first week in 25 cases. All patients suffered with arthritis. The most frequently affected joints were fingers, wrists, toes, and ankles. Eight patients were hospitalized during the acute stage, including 2 severe life-threatening cases. A total of 38 patients remained symptomatic after the tenth day with chronic peripheral rheumatism, characterized by severe joint pain and multiple tenosynovitis, with a dramatically limited ability to ambulate and carry out activities in daily life. Three patients were hospitalized at this stage for severe persistent handicap. Follow-up demonstrated slow improvement in joint pain and stiffness despite symptomatic treatment, mainly antiinflammatory and analgesic drugs. In the current series we describe 2 stages of the disease, an initial severe febrile and eruptive polyarthritis, followed by disabling peripheral rheumatism that can persist for months. We point out the possibility of transitory peripheral vascular disorders during the second stage and the occasional benefit of short-term corticosteroids. As CHIKV could spread throughout the world, all physicians should be prepared to encounter this arboviral infection.Abbreviations: CHIKV = chikungunya virus, MRI = magnetic resonance imaging, NSAIDs = nonsteroidal antiinflammatory drugs, RT-PCR = reverse transcription-polymerase chain reaction.

Chikungunya Virus Infection

Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes, mostly Aedes aegypti and Aedes albopictus. After half a century of focal outbreaks of acute febrile polyarthralgia in Africa and Asia, the disease unexpectedly spread in the past decade with large outbreaks in Africa and around the Indian Ocean and rare autochthonous transmission in temperate areas. This emergence brought new insights on its pathogenesis, notably the role of the A226V mutation that improved CHIKV fitness in Ae. albopictus and the possible CHIKV persistence in deep tissue sanctuaries for months after infection. Massive outbreaks also revealed new aspects of the acute stage: the high number of symptomatic cases, unexpected complications, mother-to-child transmission, and low lethality in debilitated patients. The follow-up of patients in epidemic areas has identified frequent, long-lasting, rheumatic disorders, including rare inflammatory joint destruction, and common chronic mood changes associated with quality-of-life impairment. Thus, the globalization of CHIKV exposes countries with Aedes mosquitoes both to brutal outbreaks of acute incapacitating episodes and endemic long-lasting disorders.

Chikungunya: A Paradigm of Emergence and Globalization of Vector-Borne Diseases

Chikungunya (CHIK) fever is a tropical arboviral disease responsible for acute polyarthritis which can last for weeks to months. In 2007, the chikungunya virus (CHIKV) reached Europe. Since the beginning of this outbreak, several million cases of chikungunya virus disease have occurred in autochthonous populations and in travelers who were diagnosed after they returned home from epidemic areas. CHIKV, usually transmitted by Aedes aegypti mosquitoes, has now been repeatedly associated with a new vector, Aedes albopictus (the Asian tiger mosquito), which has spread into tropical areas previously occupied predominantly by A aegypti, and has dispersed worldwide. Because CHIKV could spread throughout the world, all physicians should be prepared to encounter this arboviral infection, which represents a paradigm for emerging arboviral infections. In this article, the authors review different aspects of this reemerging and fascinating disease, focusing on clinical aspects and lessons from the recent large-scale outbreaks.

Morbidity and impaired quality of life 30 months after chikungunya infection: comparative cohort of infected and uninfected French military policemen in Reunion Island.

AbstractWe compared the morbidity and quality of life of military policemen (“gendarmes”) infected with chikungunya virus (CHIKV+) 30 months after contamination. We categorized the subjects in 3 groups: healed patients (n = 48), non-healed patients (n = 37, 44% of CHIKV+), and uninfected subjects (CHIKV−, n = 297).Data were self-recorded in this retrospective cohort study; they included sociodemographic information, clinical symptoms, and the Medical Outcome Study 36-item short-form health survey (MOS-SF36) quality of life questionnaire.The study population was mostly men (92%), with a median age of 42.8 years, regardless of CHIKV status. The main complaints were rheumatic symptoms (pain, stiffness, and swelling), reported 5 times more often by non-healed CHIKV+ subjects and 2–3 times more often by healed CHIKV+ subjects than by CHIKV− subjects, and fatigue. The CHIKV+ patients reported more use of health care services. Thirty months after infection, all rheumatic symptoms were more frequent and intense among CHIKV+ than among CHIKV− subjects, with a gradient of severity between healed and non-healed CHIKV+ subjects. Non-healed CHIKV+ subjects reported subsequent limitation in their activities. All dimensions of MOS-SF36 as well as physical and mental component summaries were impaired in CHIKV+ compared to CHIKV− subjects, with a decreasing gradient of impairment from non-healed to healed CHIKV+ subjects, then to CHIKV− subjects.These observations confirm the long-term impact of CHIKV infection on both physical and mental health. Questions persist regarding the duration of this impairment and the possibility of a return to “before CHIKV” health status for infected patients.

Antimalarial drug use in general populations of tropical Africa.

BackgroundThe burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine resistance. Antimalarial drug use and drug pressure are critical factors contributing to the selection and spread of resistance. The present study explores the geographical, socio-economic and behavioural factors associated with the use of antimalarial drugs in Africa.MethodsThe presence of chloroquine (CQ), pyrimethamine (PYR) and other antimalarial drugs has been evaluated by immuno-capture and high-performance liquid chromatography in the urine samples of 3,052 children (2–9 y), randomly drawn in 2003 from the general populations at 30 sites in Senegal (10), Burkina-Faso (10) and Cameroon (10). Questionnaires have been administered to the parents of sampled children and to a random sample of households in each site. The presence of CQ in urine was analysed as dependent variable according to individual and site characteristics using a random – effect logistic regression model to take into account the interdependency of observations made within the same site.ResultsAccording to the sites, the prevalence rates of CQ and PYR ranged from 9% to 91% and from 0% to 21%, respectively. In multivariate analysis, the presence of CQ in urine was significantly associated with a history of fever during the three days preceding urine sampling (OR = 1.22, p = 0.043), socio-economic level of the population of the sites (OR = 2.74, p = 0.029), age (2–5 y = reference level; 6–9 y OR = 0.76, p = 0.002), prevalence of anti-circumsporozoite protein (CSP) antibodies (low prevalence: reference level; intermediate level OR = 2.47, p = 0.023), proportion of inhabitants who lived in another site one year before (OR = 2.53, p = 0.003), and duration to reach the nearest tarmacked road (duration less than one hour = reference level, duration equal to or more than one hour OR = 0.49, p = 0.019).ConclusionAntimalarial drug pressure varied considerably from one site to another. It was significantly higher in areas with intermediate malaria transmission level and in the most accessible sites. Thus, P. falciparum strains arriving in cross-road sites or in areas with intermediate malaria transmission are exposed to higher drug pressure, which could favour the selection and the spread of drug resistance.

Adverse events following pandemic influenza vaccine Pandemrix® reported in the French military forces--2009-2010.

BACKGROUNDnIn the face of the A(H1N1) 2009 influenza pandemic, in October 2009 the French military health service (SSA) initiated a large vaccination campaign with Pandemrix(®) vaccine in the military forces. The aim of this study was to describe vaccine adverse events (VAE) reported during this campaign.nnnMETHODSnVAE and the number of people vaccinated were surveyed by the SSA Epidemiological network across all military forces during the campaign, from October 2009 to April 2010. For each case, a notification form was completed, providing patient and clinical information. Three types of VAE were considered: non-serious, serious and unexpected.nnnRESULTSnThere were 315.4 reported VAE per 100,000 vaccinations. Vaccination and VAE incidence rate peaks coincided with influenza epidemic peak in early December. The number of injected doses was 49,138, corresponding to a 14.5% vaccination coverage among military personnel, and 155 VAE were reported, including 5 serious VAE (1 Guillain-Barre syndrome, 2 malaises and 1 convulsive episode). Most VAE were non-serious (97.1%). Among these, 6 cases of local, rapidly regressive paresthesia were observed.nnnDISCUSSIONnThe military VAE surveillance system constitutes the only observatory on benign VAE in France. The reporting rate was much higher after the pandemic vaccine than after the seasonal vaccine, which may be a reflection of stimulated reporting. This report provides a useful description of VAE among military personnel during a mass emergency vaccination program, showing that the tolerance of the pandemic vaccine appeared acceptable.

Persisting Mixed Cryoglobulinemia in Chikungunya Infection

Background Chikungunya virus (CHIKV), an arbovirus, is responsible for a two-stage disabling disease, consisting of an acute febrile polyarthritis for the first 10 days, frequently followed by chronic rheumatisms, sometimes lasting for years. Up to now, the pathophysiology of the chronic stage has been elusive. Considering the existence of occasional peripheral vascular disorders and some unexpected seronegativity during the chronic stage of the disease, we hypothesized the role of cryoglobulins. Methods From April 2005 to May 2007, all travelers with suspected CHIKV infection were prospectively recorded in our hospital department. Demographic, clinical and laboratory findings (anti-CHIKV IgM and IgG, cryoglobulin) were registered at the first consultation or hospitalization and during follow-up. Results Among the 66 travelers with clinical suspicion of CHIKV infection, 51 presented anti-CHIKV IgM. There were 45 positive with the serological assay tested at room temperature, and six more, which first tested negative when sera were kept at 4°C until analysis, became positive after a 2-hour incubation of the sera at 37°C. Forty-eight of the 51 CHIKV-seropositive patients were screened for cryoglobulinemia; 94% were positive at least once during their follow-up. Over 90% of the CHIKV-infected patients had concomitant arthralgias and cryoglobulinemia. Cryoglobulin prevalence and level drop with time as patients recover, spontaneously or after short-term corticotherapy. In some patients cryoglobulins remained positive after 1 year. Conclusion Prevalence of mixed cryoglobulinemia was high in CHIKV-infected travelers with long-lasting symptoms. No significant association between cryoglobulinemia and clinical manifestations could be evidenced. The exact prognostic value of cryoglobulin levels has yet to be determined. Responsibility of cryoglobulinemia was suspected in unexpected false negativity of serological assays at room temperature, leading us to recommend performing serology on pre-warmed sera.

Acute pancreatitis: A rare complication of acute hepatitis E

Hepatitis E is an emerging imported disease in Europa but autochthonous cases are described for some years. Extra-hepatic associated manifestations are published. We report a case of acute necrotizing pancreatitis associated with imported acute viral E hepatitis (genotype 1a) in a 26 years old French man travelling and originated from Pakistan. The outcome is favourable spontaneously in two months. This life-threatening hepatitis E related complication is unknown in Europa where genotype 3 virus strains prevail. The clinical presentation is stereotyped with the onset of pancreatitis in the second or third weeks of hepatitis evolution in an Indian male in his second or third decade infected with genotype 1 strain. No pancreatitis-related death is reported in the 13 previous reported cases.

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline

ABSTRACT The distribution and range of 50% inhibitory concentrations (IC50s) of doxycycline were determined for 747 isolates obtained between 1997 and 2006 from patients living in Senegal, Republic of the Congo, and Gabon and patients hospitalized in France for imported malaria. The statistical analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to doxycycline. A triple normal distribution was fitted to the data using a Bayesian mixture modeling approach. The IC50 geometric mean ranged from 6.2 μM to 11.1 μM according to the geographical origin, with a mean of 9.3 μM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC50 mean of 4.9 μM (±2.1 μM [standard deviation]); component B, with an IC50 mean of 7.7 μM (±1.2 μM); and component C, with an IC50 mean of 17.9 μM (±1.4 μM). According to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 μM.

Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

BackgroundThe aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) and piperaquine (PPQ), as new components of artemisinin-based combination therapy (ACT), to define susceptibility baseline, ii) their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ), lumefantrine (LMF), mefloquine (MQ), artesunate (AS) and dihydroartemisinin (DHA) against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii) in vitro cross-resistance with other quinoline drugs, chloroquine (CQ) or quinine (QN).MethodsThe susceptibility of the 181 P. falciparum isolates to the nine anti-malarial drugs was assessed using the standard 42-hours 3H-hypoxanthine uptake inhibition method.ResultsThe IC50 values for PND ranged from 0.55 to 80.0 nM (geometric mean = 19.9 nM) and from 11.8 to 217.3 nM for PPQ (geometric mean = 66.8 nM). A significant positive correlation was shown between responses to PPQ and PND responses (rho = 0.46) and between PPQ and MDAQ (rho = 0.30). No significant correlation was shown between PPQ IC50 and responses to other anti-malarial drugs. A significant positive correlation was shown between responses to PND and MDAQ (rho = 0.37), PND and LMF (rho = 0.28), PND and QN (rho = 0.24), PND and AS (rho = 0.19), PND and DHA (rho = 0.18) and PND and CQ (rho = 0.16). All these coefficients of correlation are too low to suggest cross-resistance between PPQ or PND and the other drugs.ConclusionsIn this study, the excellent anti-malarial activity of PPQ and PND was confirmed. The absence of cross-resistance with quinolines and artemisinin derivatives is consistent with the efficacy of the combinations of PPQ and DHA or PND and AS in areas where parasites are resistant to conventional anti-malarial drugs.