A 30-year-old caucasian woman, without past medical history or known drug use, was admitted to the emergency department for persistent fever and arthralgias. The laboratory analysis showed moderate hypoosmolar hyponatremia (Na: 132 mmol/L, osmolality: 239 mOsm/L), normal sodium excretion (<20mmol/L), and a high urinary osmolality (415 mOsm/L). Later, she deteriorated with seizures and deeper hyponatremia (Na: 113 mmol/L) and so was moved to the critical care unit. At first, no obvious aetiology was found, the patient was euvolemic, as she was well hydrated and lacked concerning findings of heart failure, renal disease, or liver cirrhosis. A syndrome of inappropriate diuresis (SIAD) was proposed, and corrective measures were started immediately to reduce her hyponatremia, including restriction of fluid intake. The administration of intravenous hypertonic saline solution permitted normal neurological status to be restored and corrected the sodium concentration but induced reversible acute renal failure. Further investigation revealed that the patient had ingested 8 g ibuprofen two days before admission. After other aetiologies were ruled out, drug-induced SIAD due to ibuprofen was the most likely diagnosis for this patient. SIAD-associated hyponatremia and acute renal failure are rare side effects of nonsteroidal anti-inflammatory drugs, particularly in young people. Therefore, this case may represent a unique case of NSAID-induced SIAD and highlight the need to obtain thorough medication histories and exclude all other potential causes in hyponatremic patients.

Hyperbilirubinemia is an expected side-effect of atazanavir (ATV) in HIV-infected patients, resulting from the competition with the uridine diphosphate glucuronosyltransferase (UGT1A1 enzyme) that conjugates the bilirubin [1]. The rise in indirect plasmatic bilirubin is commonly moderate and benign but can induce severe jaundice in patients with underlying Gilbert's syndrome [2]. Incidence of ATV-associated hyperbilirubinemia grade 3 or 4 (the highest level according to the AIDS Clinical Trials Group guidelines for total bilirubin levels) is estimated the same in white patients as in Asian ones [3], despite a far much lower frequency of the common polymorphism for Gilbert's Disease (UGT1A1*28 allele) in this last population [4]. Genetic factors more specific to the Asian ethnic background have been investigated but a few studies are conclusive [5] and none of them have tested patients for hemolysis, probably because of the lack of anemia. We report for the first time a Canton glucose-6-phosphate dehydrogenase (G6PD) deficiency with compensated hemolysis revealed by a severe ATV-associated jaundice in an Asian HIV-infected patient. A 34-year-old Thai man was diagnosed AIDS with Pneumocystis jiroveci pneumonia in July 2004 (CD4 cell count – 8 cells/mm3 and HIV-RNA plasma viral load – 500 000 copies/ml). After a 1-month treatment with trimethoprim–sulfamethoxazole and highly active antiretroviral therapy (HAART) including zidovudine, lamivudine, ritonavir and lopinavir, he developed aplasia complicated with Mycobacterium avium bacteriemia. Bone marrow findings were consistent with drug toxicity. Treatment adaptation (switch to clarithromycin, rifabutin, ethambutol, didanosine, lamivudine, ritonavir, lopinavir and prophylaxis by atovaquone) lead to cell-count recovery and sustained immunity restoration (CD4 cell count >500/mm3 and HIV-RNA load undetected). In January 2009, HAART was switched to a once-daily dosing therapy with a favorable effect on lipid profile: abacavir, lamivudine and ritonavir-boosted ATV. Shortly afterwards, he presented for the first time with severe asymptomatic jaundice. Laboratory data found hyperbilirubinemia up to 60 μmol/l with indirect bilirubin over 54 μmol/l, whereas hemoglobin level and CD4 cell count remained stable (14 g/dl) (Fig. 1). No associated hepatic disease was found (negative for hepatitis A, B, C and E, no liver cytolysis nor cholestasis and normal ultrasonography). ATV was monitored twice without overdosing (Fig. 1). Molecular analysis of the UGTA1A gene performed by restrictive analysis following PCR showed heterozygosis for UGT1A1*28 polymorphism. Further biological investigations revealed absent haptoglobin, elevated LDH to 550 U/l [normal range (240–480) U/l] and reticulocytosis (reticulocytes: 122 Giga/l). Explorations of hemolysis found no red-cell membrane defects, no hemoglobinopathy (studied by electrophoresis) and normal pyruvate kinase activity [19 U/g Hb; normal range (5–21)]. Malaria tests and direct antiglobulin test (Coombs’ test) were negative. Deficient G6PD activity in erythrocytes (Randox reagent PD410) was detected and direct DNA sequencing identified a G6PD Canton variant (NM_000402; c.1376 G→T). Neither broad beans, nor other oxidative stressor had been consumed. In June 2010, ATV was switched to raltegravir, whereas abacavir and lamivudine were kept. Normalization of bilirubin level and hemolysis settings was immediately observed and notification to the French Regional Pharmacovigilance Center was made.Fig. 1: Bilirubin and hemoglobin levels with antiretroviral agent atazanavir plasmatic concentrations measured between November 2007 and July 2010.ATV, atazanavir; Hb, hemoglobin.This is the first report of severe ATV-associated jaundice in an Asian HIV patient with underlying heterozygous UGT1A1*28 polymorphism associated with Canton G6PD deficiency. The contribution of the UGT1A1*28 allele alone to grade 3–4 hyperbilirubinemia under ATV was found only significant for homozygotes [2]. This genotype is rarely encountered in Asians [4], among whom the unexpected high incidence of severe ATV-associated jaundice [3] must be due to additional factors. Interestingly, studies on neonatal hyperbilirubinemia found that G6PD deficiency or Gilbert's mutations, alone, did not predispose to jaundice in the newborns, whereas G6PD-deficient neonates who also were heterozygotes or homozygotes for the variant UGT1A1*28 did significantly increase indirect bilirubinemia [6]. Thus, Gilbert's syndrome and G6PD deficiency are both common inherited conditions, and their combination on a genetic background and under environmental factors may induce hemolysis [7]. One trigger, more especially in Asian adults, could be ATV. In our G6PD-deficient patient, the absence of hemolytic anemia under cotrimoxazole could result from a too-short exposure, have been masked by the bone marrow toxicity, or be explained by the Canton variant. The present case strengthens the recent recommendation of Serpa et al.[8] to perform G6PD testing in HIV patients from the start of the disease course. Facing severe ATV-associated hyperbilirubinemia, hemolysis should be investigated, even without anemia, or if UGT1A1*28 polymorphism is found, considering moreover that a wide Gilbert's genotype analysis is not affordable in classical laboratories. ATV could be the first antiretroviral oxidant drug. Acknowledgement Conflicts of interest There are no conflicts of interest.

We 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.

Les hemoglobinopathies sont les maladies genetiques les plus frequentes. Leur repartition geographique est superposee aux zones d'endemies palustres. Les syndromes drepanocytaires graves et les thalassemies majeures necessitent un diagnostic rapide. L'objectif de cet article est de decrire les techniques de diagnostic de premiere intention disponibles dans les laboratoires non specialises et de sensibiliser le lecteur aux pieges de l'interpretation.

To the Editor: We read with great interest the letter published by Peevers et al. (1) about the hepatotoxicity of Khat, a potentially severe complication of Khat chewing reported recently (2, 3). In our experience in Djibouti Republic (East Africa) between 2001 and 2007, where khat chewing is a daily recreational activity and a public health problem, some colleagues and I never saw any hepatitis induced by khat. In the French Military Hospital Bouffard, during my stay between 2005 and 2007, we registered 12 acute hepatitis: nine viral hepatitis (A or E), two exertional heat stroke and one Wilson disease (unpublished data). Furthermore, in 1979, Ardouin et al. (4) analysed 204 hepatic biopsies especially realized in heavy khat consumers also in Djibouti: no significant lesion, except for sinusoid capillary dilatation and congestion, but no cholestasis, lobular necrosis, fibrosis or cirrhosis was found. We are surprised by the clinical and histopathological differences between hepatotoxicity of khat chewing in UK in Somali immigrants (1–3), who never presented such accidents before they immigrated to UK (2), and its apparent absence in East Africa (4). We are also surprised by the disease severity (1–3) regarding the low amount of khat intakes in those patients (1, 3) when compared with the absence of hepatotoxicity in heavy daily consumers in our experience in Djibouti. In UK, the association with alcohol or other drugs’ consumption, especially 3,4methylenedioxy-methylamphetamine (ecstasy), may interfere and must be ruled out by systematic urinary toxicological researches, plasmatic desialotransferrin dosage and with distomatosis serology to make it clear. Personal or family questioning is not reliable in Muslim Somali immigrants not allowed to drink alcohol or to take drugs. Furthermore, in our experience, Khat is rarely chewed alone because of its bad taste and for example, in Djibouti, Coca Cola (Avenue Georges Pompidou, Djibouti-République de Djibouti) drinking is always associated, so why not alcohol? We may also imagine that other drugs could be taken to avoid the khat depressant effects in the hours following chewing. A different toxicity between fresh khat leaves chewed in East Africa and imported ones in UK may also be discussed. Finally, we agree with the hypothesis of a potential contamination by pesticides or other contaminants during transport (1). Hence, it would also be of great interest to determine the era of production of khat chewed in UK. In our opinion, a detailed toxicological inquest must be undertaken before speaking about khat hepatotoxicity in humans.

Anemia is the most common pathology encountered in hematology. Etiologies are numerous, so it is important to adopt a rigorous approach. Complementary examinations must be specific to the clinical situation in order to determine the mechanisms on the one hand and decide the therapeutic management on the other. We report the observation of a case of sudden onset of profound pancytopenia. Investigation led to the diagnosis of major folic acid deficiency with favorable evolution. Through this case, we describe the diagnostic approach towards anemia and the mechanisms involved in the formation of folate deficiency.

Purpose 5-Fluorouracil (5-FU) is a mainstay for treating various solid tumours in adults, including digestive and head and neck cancers. 5-FU-related toxicities usually include haematological, digestive and cutaneous features. Additionally, 5-FU has been described as being potentially neurotoxic in patients, but these side effects are quite rare in clinical practice. Here, we report two cases of sudden and unpredictable drug-induced neurotoxicities that occurred in patients undergoing their first course of 5-FU-based chemotherapy. Patients and methods None of these patients had any previous neurological disorder history, and both were treated following standard regimen (LV-5-FU2 and TPF for patient 1 and 2, respectively). Neurotoxicity included drowsiness, acute confusion plus dysarthria for the first patient and seizure, confusion and signs of metabolic encephalopathy for the second one. In addition, typical 5-FU-related severe toxicities (e.g. neutropenia and mucosities) were observed. Both patients slowly recovered from these neurological toxicities under supportive treatment. It was assumed that overexposure to 5-FU could explain the severe toxicities encountered. To test this hypothesis, we retrospectively evaluated the dihydropyrimidine dehydrogenase (DPD) activity of these patients on a phenotypic basis. Results Evaluation of the uracil-to-di-hydrouracil (U/UH2) ratio in plasma revealed a profound DPD deficiency syndrome in both patients. Conclusion These cases suggest that 5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features. It implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of DPD deficiency before starting any 5-FU-containing chemotherapy so as to prevent such side effects in the future.

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.

Background Plasmodium ovale is responsible for 5% of imported malaria in French travellers. The clinical and biological features of six clustered cases of P. ovale malaria in an army unit of 62 French soldiers returning from the Ivory Coast are reported. Case report All patients were symptomatic and developed symptoms on average 50 days after their return and 20 days after the end of chemoprophylaxis (doxycycline). Clinical features included fever (6/6), mostly tertian (4/6), aches (6/6), nausea (3/6), abdominal pain (2/6), diarrhoea (2/6), or cough (2/6). Thrombocytopaenia was lower than 100,000/mm 3 in half the cases only, and the haemoglobin count was normal for all patients. The diagnosis was made after at least three thick and thin blood smear searches. Parasitaemia was always lower than 0.5%. All rapid diagnostic tests were negative for HRP2 and pLDH antigens. Discussion Plasmodium ovale malaria is currently a problem to diagnose in travellers, notably in French soldiers returning from the Ivory Coast. Early attempts at diagnosis are difficult due to the lack of specific clinical features, the rarity of biological changes and the poor sensitivity of diagnostic tools to detect low parasitaemia. Thus, the diagnosis is commonly delayed or missed. Physicians should be aware of this diagnostic challenge to avoid relapses and provide prompt and adequate treatment with chloroquine and radical cure with primaquine.

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 degrees C until analysis, became positive after a 2-hour incubation of the sera at 37 degrees 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.

The acute stage of infection with chikungunya virus, which is characterized of fever, polyarthritis, and occasional rash, can be complicated by myocarditis, as reported in a 21-year-old woman. Persisting changes on cardiac magnetic resonance imaging one year after disease onset could lead to delayed myocardial damage. An unexpected delayed increase in dilated cardiomyopathy may be observed in countries affected by the outbreak of chikungunya virus disease during 2005-2007.

In recent decades Marseilles, through immigration, has become the largest Comorian city outside the archipelago. It is also home to a faculty of medicine that has made infectious diseases one of its fields of excellence. During the last two years, Marseilles has spearheaded the metropolitan French response to the Chikungunya crisis in the Indian Ocean region, and especially in the Reunion Island and Mayotte. Laveran military teaching hospital (Hôpital d'instruction des armées, HIA) has managed one of the largest metropolitan cohorts. Its teams have also reported the broad clinical spectrum of the disease in its later stages, and especially the high incidence of incapacitating tenosynovitis and distal arthritis, as well as the occurrence of a transient acrosyndrome during the second and third months in nearly one-quarter of patients. Importantly, they have also identified a mixed cryoglobulin in more than 90% of patients, the level of which matches clinical symptoms and is sensitive to systemic steroid therapy. This discovery opens the way to a better understanding of the pathophysiology of this viral disease. The Tropical Virology laboratory of the Tropical Medicine Institute of the Army health service (IMTSSA), which has close links with the national references center (CNRS) arbovirus laboratory, has developed new diagnostic tools, notably based on RT-PCR. Together with national reference center (CNRS), the laboratory produces and supplies antigens for Chikungunya serological tests in metropolitan France and overseas. It has taken into account the presence of cryoglobulins, which can lead to false-negative results in infected patients, and has considerably increased the diagnostic yield of serological techniques. The laboratory's fundamental research focuses on genomic characterization of viral variants isolated from humans and from the vector, and also on viral protease expression, for functional studies and antiviral candidate drug selection. The laboratory also collaborates with clinical teams in Reunion and metropolitan France working on humoral and cellular immune responses and on the different clinical forms of the disease. The Epidemiology and Public Health Department of IMTSSA conducted an epidemiological study of all gendarmes working in Reunion at the end of the epidemic (June 2006). This study, done in partnership with the tropical virology laboratory and CNRS, is helping to complete the clinical description of the epidemic, in an unbiased population. In 2007, it will form the basis for a prospective cohort study in which these patients will be monitored for several years to better document the chronic phase of the disease in a population with excellent healthcare access. Finally, the department has provided the civil authorities with advice and support in disease-control operations in Reunion. Communication played an important role in the management of this crisis, showing how crucial it now is for healthcare professionals to develop relevant skills. The Army Health Service in Maarseilles was never isolated from its university partners, as witnessed by clinical collaboration between Laveran HIA and CHU Nord (a Marseilles teaching hospital) and by virological cooperation between the IMTSSA and Etablissement français du sang (EFS) laboratories. This experience is highly encouraging with respect to the creation in Marseilles of a healthcare research network (RTRS) devoted to tropical and emerging infectious diseases.