Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.

BACKGROUND: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. METHODS: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. RESULTS: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). CONCLUSIONS: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.

Clinical Management of Ebola Virus Disease in the United States and Europe.

BACKGROUND: Available data on the characteristics of patients with Ebola virus disease (EVD) and clinical management of EVD in settings outside West Africa, as well as the complications observed in those patients, are limited. METHODS: We reviewed available clinical, laboratory, and virologic data from all patients with laboratory-confirmed Ebola virus infection who received care in U.S. and European hospitals from August 2014 through December 2015. RESULTS: A total of 27 patients (median age, 36 years [range, 25 to 75]) with EVD received care; 19 patients (70%) were male, 9 of 26 patients (35%) had coexisting conditions, and 22 (81%) were health care personnel. Of the 27 patients, 24 (89%) were medically evacuated from West Africa or were exposed to and infected with Ebola virus in West Africa and had onset of illness and laboratory confirmation of Ebola virus infection in Europe or the United States, and 3 (11%) acquired EVD in the United States or Europe. At the onset of illness, the most common signs and symptoms were fatigue (20 patients [80%]) and fever or feverishness (17 patients [68%]). During the clinical course, the predominant findings included diarrhea, hypoalbuminemia, hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia; 14 patients (52%) had hypoxemia, and 9 (33%) had oliguria, of whom 5 had anuria. Aminotransferase levels peaked at a median of 9 days after the onset of illness. Nearly all the patients received intravenous fluids and electrolyte supplementation; 9 (33%) received noninvasive or invasive mechanical ventilation; 5 (19%) received continuous renal-replacement therapy; 22 (81%) received empirical antibiotics; and 23 (85%) received investigational therapies (19 [70%] received at least two experimental interventions). Ebola viral RNA levels in blood peaked at a median of 7 days after the onset of illness, and the median time from the onset of symptoms to clearance of viremia was 17.5 days. A total of 5 patients died, including 3 who had respiratory and renal failure, for a mortality of 18.5%. CONCLUSIONS: Among the patients with EVD who were cared for in the United States or Europe, close monitoring and aggressive supportive care that included intravenous fluid hydration, correction of electrolyte abnormalities, nutritional support, and critical care management for respiratory and renal failure were needed; 81.5% of these patients who received this care survived.

High heterogeneity in community-acquired pneumonia inclusion criteria: does this impact on the validity of the results of randomized controlled trials?

BACKGROUND: There is no consensus on the most accurate combination of diagnostic criteria to define community acquired pneumonia (CAP). We describe inclusion criteria in randomized controlled trials (RCT) of CAP and assess their performance for the diagnosis of formally identified CAP. METHODS: RCTs related to CAP recorded on ClinicalTrials.gov were analysed. Due to high heterogeneity, we divided close CAP inclusion criteria into patterns (i.e. combinations of inclusion criteria). To assess their diagnostic performances, these CAP definition patterns were applied to a reference population of 319 suspected CAP patients, in whom the CAP diagnosis had been confirmed (n = 163) or excluded (n = 156) by an adjudication committee after a systematic thoracic CT-scan and a 28-day follow-up period. RESULTS: In the 47 RCTs included in the analysis, 42 different CAP inclusion criteria combinations were identified and 8 patterns created. This heterogeneity was not explained either by the trials' methodology or by their objectives. When applied to the reference population, the performance ranges of the 8 definition patterns were 9.8-56.4% for sensitivities, 56.4 97.4% for specificities, 63.6 83.6% for positive predictive values and 50.8-66.7% for negative predictive values. None of the CAP definitions had both sensitivity and specificity superior to 65%. Depending on the CAP definition, the rate of included patients without CAP ("false positives") ranged from 1 to 21%. CONCLUSIONS: CAP diagnostic criteria within RCTs are heterogeneous, which may have far-reaching consequences on validity of RCT results.

Occupational Exposures to Ebola Virus in Ebola Treatment Center, Conakry, Guinea.

We report 77 cases of occupational exposures for 57 healthcare workers at the Ebola Treatment Center in Conakry, Guinea, during the Ebola virus disease outbreak in 2014-2015. Despite the high incidence of 3.5 occupational exposures/healthcare worker/year, only 18% of workers were at high risk for transmission, and no infections occurred.

Rhabdomyolysis in Ebola Virus Disease. Results of an Observational Study in a Treatment Center in Guinea.

BACKGROUND: The pathogenesis of Ebola virus disease (EVD) remains unclear. The sporadic nature of Ebola outbreaks and their occurrence in resource-limited settings have precluded the acquisition of extensive clinical and laboratory data. Rhabdomyolysis during EVD has been suggested to occur in previous studies showing increased aspartate aminotransferase-alanine aminotransferase ratios, but, to date, has not been confirmed with creatine kinase (CK) assays. METHODS: We performed an observational study of 38 patients admitted to an Ebola treatment center from January to April 2015. CK values from patients with confirmed EVD were compared with those in patients without confirmed EVD. A panel of other analyses were also performed. In patients with EVD, characteristics were compared between survivors and nonsurvivors. RESULTS: High levels of CK were more frequent in patients with EVD than in those without (P = .002), and rhabdomyolysis was more frequent (59% vs 19%, respectively; P = .03). CK levels >5000 U/L were observed in 36% of patients with EVD. Also in patients with EVD, fatal outcome was significantly associated with higher creatinine and bilirubin levels, international normalized ratio, and viral load. CONCLUSIONS: Rhabdomyolysis is a frequent disorder in EVD and seems to be more common than in other viral infections. It may contribute to the renal failure observed in nonsurviving patients. More studies are needed to determine the impact of rhabdomyolysis on EVD outcome.

Arboviral and other illnesses in travellers returning from Brazil, June 2013 to May 2016: implications for the 2016 Olympic and Paralympic Games.

We evaluated EuroTravNet (a GeoSentinel subnetwork) data from June 2013 to May 2016 on 508 ill travellers returning from Brazil, to inform a risk analysis for Europeans visiting the 2016 Olympic and Paralympic Games in Brazil. Few dengue fever cases (n = 3) and no cases of chikungunya were documented during the 2013-15 Brazilian winter months, August and September, the period when the Games will be held. The main diagnoses were dermatological (37%), gastrointestinal (30%), febrile systemic illness (29%) and respiratory (11%).

Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013.

Artesunate is the most effective treatment for severe malaria. However, delayed-onset hemolytic anemia has been observed in ≈20% of travelers who receive artesunate, ≈60% of whom require transfusion. This finding could discourage physicians from using artesunate. We prospectively evaluated a cohort of 123 patients in France who had severe imported malaria that was treated with artesunate; our evaluation focused on outcome, adverse events, and postartesunate delayed-onset hemolysis (PADH). Of the 123 patients, 6 (5%) died. Overall, 97 adverse events occurred. Among the 78 patients who received follow-up for >8 days after treatment initiation, 76 (97%) had anemia, and 21 (27%) of the 78 cases were recorded as PADH. The median drop in hemoglobin levels was 1.3 g/dL; 15% of patients with PADH had hemoglobin levels of <7 g/dL, and 1 required transfusion. Despite the high incidence of PADH, the resulting anemia remained mild in 85% of cases. This reassuring result confirms the safety and therapeutic benefit of artesunate.

[Ebola virus disease and accredited specialist health institutions]. / Maladie à virus Ebola et établissement de santé référent habilité.

Ebola virus disease (EVD) went in the space of a few months from being a forgotten tropical disease to a global "health emergency". The scope of this Ebola virus epidemic (Zaire strain), which has broken out in West Africa, its spread and the high number of deaths reported among frontline health workers are unprecedented. This article describes how a specialist hospital deals with imported cases of EVD.

Molecular characterization of blaNDM-1 in a sequence type 235 Pseudomonas aeruginosa isolate from France.

An NDM-1 carbapenemase-producing Pseudomonas aeruginosa isolate was recovered from a patient hospitalized in France after a previous hospitalization in Serbia. Genetic studies revealed that the blaNDM-1 gene was surrounded by insertion sequence ISAba125 and a truncated bleomycin resistance gene. This blaNDM-1 region was a part of the variable region of a new complex class 1 integron bearing IS common region 1 (ISCR1). The presence of ISPa7 upstream of this integron suggests insertion in a chromosomally located Tn402-like structure.

The 2009 A(H1N1) influenza pandemic in the French Armed Forces: evaluation of three surveillance systems.

BACKGROUND: The French military forces had to modify their epidemiological surveillance systems at the time of the 2009 A(H1N1) influenza pandemic. The aim of this article was to present an evaluation of the different systems used. METHODS: Two influenza surveillance systems are usually used in the French forces: one permanent (Surveillance épidémiologique des armées or SEA) and one seasonal (Système militaire d'observation de la grippe or SMOG). The pandemic required the implementation of a daily surveillance system (Surveillance quotidienne--SQ), which aimed to monitor disrupted activity owing to 2009 A(H1N1) influenza. The qualitative evaluation of these three systems during the period from September 2009 to February 2010 was performed using 11 criteria based on the list defined by Centers for Disease Control and Prevention of Atlanta. RESULTS: Although it included only 30 sentinel units vs. 320 for the other systems, the SMOG system was the best-performing system in terms of relevance, feasibility, efficacy, quality of data, usefulness, acceptability, efficiency and cost/benefits/costs ratio. The SQ proved very expensive in terms of logistics. CONCLUSION: The SQ did not bring any significant advantage compared with the weekly surveillance schemes. In the eventuality of another similar episode, influenza surveillance could be significantly improved by using the SMOG system extended to more units for better geographical coverage.

[Update on Mycobacterium bovis infections in France: 4 cases reports]. / Actualités de l'infection à Mycobacterium bovis en France : à propos de 4 cas.

Mycobacterium bovis (M. bovis) is a cause of zoonosis. It is rare in developed countries since cattle control. We report four cases of M. bovis infection in people aged more 60 years. They were probably infected during infancy, consuming unpasteurized milk. It is the main transmission mode in developing countries where veterinary controls aren't made. M. bovis infections clinical aspects are varied and treatment is complicated by natural pyrazinamide resistance. Recent diagnostic methods using molecular biology are quick and specific and facilitate identification.

Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

Travel-related infections presenting in Europe: A 20-year analysis of EuroTravNet surveillance data.

BACKGROUND: Disease epidemiology of (re-)emerging infectious diseases is changing rapidly, rendering surveillance of travel-associated illness important. METHODS: We evaluated travel-related illness encountered at EuroTravNet clinics, the European surveillance sub-network of GeoSentinel, between March 1, 1998 and March 31, 2018. FINDINGS: 103,739 ill travellers were evaluated, including 11,239 (10.8%) migrants, 89,620 (86.4%) patients seen post-travel, and 2,880 (2.8%) during and after travel. Despite increasing numbers of patient encounters over 20 years, the regions of exposure by year of clinic visits have remained stable. In 5-year increments, greater proportions of patients were migrants or visiting friends and relatives (VFR); business travel-associated illness remained stable; tourism-related illness decreased. Falciparum malaria was amongst the most-frequently diagnosed illnesses with 5,254 cases (5.1% of all patients) and the most-frequent cause of death (risk ratio versus all other illnesses 2.5:1). Animal exposures requiring rabies post-exposure prophylaxis increased from 0.7% (1998-2002) to 3.6% (2013-2018). The proportion of patients with seasonal influenza increased from zero in 1998-2002 to 0.9% in 2013-2018. There were 44 cases of viral haemorrhagic fever, most during the past five years. Arboviral infection numbers increased significantly as did the range of presenting arboviral diseases, dengue and chikungunya diagnoses increased by 2.6% and 1%, respectively. INTERPRETATION: Travel medicine must adapt to serve the changing profile of travellers, with an increase in migrants and persons visiting relatives and friends and the strong emergence of vector-borne diseases, with potential for further local transmission in Europe. FUNDING: This project was supported by a cooperative agreement (U50CK00189) between the Centers for Disease Control and Prevention to the International Society of Travel Medicine (ISTM) and funding from the ISTM and the Public Health Agency of Canada.

Doxycycline failure in lymphogranuloma venereum.

Lymphogranuloma venereum (LGV) cases are currently re-emerging in the homosexual community, particularly in HIV-seropositive patients. The standard treatment for this infection, which is caused by Chlamydia trachomatis L1, L2 and L3 serotypes, is a 3-week doxycycline regimen. The case is reported of a male patient presenting with LGV, who was rapidly cured with moxifloxacin treatment after failure of extended treatment with cyclines. This fluoroquinolone is known to be highly active in vitro on the LGV pathogenic agent. Thus it may be a useful alternative when doxycycline treatment results in failure.

The challenge of diagnosing Plasmodium ovale malaria in travellers: report of six clustered cases in French soldiers returning from West Africa.

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/mm3 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.

[Tuberculous meningitis: diagnosis and therapeutic difficulties]. / Méningites tuberculeuses: difficultés diagnostiques et thérapeutiques.

Tuberculosis remains a public-health problem in 2010 with 9 millions cases and 1,7 million deaths worldwide each year. Tuberculosis meningitis is rare (0.5 to 1%) but is associated with high mortality and disability among survivors. An early starting of treatment is crucial. Despite molecular biology methods, microbiological diagnosis remains a challenge for the biologist. We report here 2 cases of tuberculous meningitis with different clinical and biological presentations, which underline diagnosis and therapeutic difficulties encountered in the management of this disease. The first one occurred in an HIV infected patient and the second one was caused by a multidrug-resistant strain. Clinical issues were severe with important neurological residual disability and death. Biological methods available for tuberculous meningitis diagnosis are exposed.

[Dengue fever: an emerging infectious disease]. / Dengue : une infection émergente.

Dengue fever: an emerging infectious disease. Dengue fever is caused by an arbovirus of the family Flaviviridae and the genus Flavivirus, of which there are 4 serotypes (DEN-1, DEN-2, DEN-3, DEN-4). It is transmitted by the bite of a diurnal mosquito of the genus Aedes, mainly A. aegypti and A. albopictus. An increasing cause of acute fever in travellers, it threatens to emerge in temperate regions where competent mosquitoes (Aedes) are established. Dengue fever is characterized by its clinical polymorphism ranging from asymptomatic to severe forms, which are rare in travellers. Its definite diagnosis is based on virological tests selected according to the stage of the disease and the kinetics of the virus. Its treatment is only symptomatic. It is a notifiable disease in mainland France and is subject to a plan to combat its spread and to specific surveillance in the overseas departments. Dengue prevention is based on the application of personal anti-vectorial protection measures among travellers, awareness-raising among health professionals and social mobilization to combat larval gites in endemic regions or regions colonized by Aedes. In France, the tetravalent vaccine Dengvaxia, which is licensed in France, is not recommended for people residing in overseas departments and for travelers to endemic areas.

Dengue : une infection émergente. La dengue est due à un arbovirus de la famille des Flaviviridae et du genre Flavivirus, dont il existe quatre sérotypes (DEN-1, DEN-2, DEN-3, DEN-4). Elle est transmise par la piqûre d'un moustique diurne du genre Aedes, essentiellement A. aegypti et A. albopictus. Cause croissante de fièvre aiguë chez les voyageurs, elle menace d'émerger dans les régions tempérées ou des moustiques compétents ( Aedes) sont implantés. La dengue est caractérisée par son polymorphisme clinique allant de formes asymptomatiques à des formes graves, rares chez le voyageur. Son diagnostic de certitude repose sur des examens virologiques choisis en fonction du stade de la maladie et de la cinétique du virus. Son traitement est uniquement symptomatique. Il s'agit d'une maladie à déclaration obligatoire en métropole qui fait l'objet d'un plan de lutte antidissémination et d'une surveillance spécifique dans les départements ultramarins. La prévention de la dengue repose sur l'application des mesures de protection personnelle antivectorielle chez les voyageurs, une sensibilisation des professionnels de santé et une mobilisation sociale pour lutter contre les gîtes larvaires dans les régions endémiques ou colonisées par des Aedes. En France, le vaccin tétravalent Dengvaxia, homologué, n'est cependant pas recommandé chez les personnes qui résident dans les départements ultramarins ni chez les voyageurs se rendant dans des zones endémiques.

Pathological rupture of the spleen in malaria: analysis of 55 cases (1958-2008).

BACKGROUND: Splenic rupture during acute malaria is rare but underreported. Because splenic rupture occurs mostly in non-immune adults, ongoing malaria elimination efforts may paradoxically increase the proportion of Plasmodium-infected patients suffering from this life-threatening complication. The pathogenesis and optimal patient management are still debated. METHOD: We collected and analysed reports of pathological rupture of the spleen associated with malaria published over the last 50 years in five languages. RESULTS: Fifty-five cases were reported, due to Plasmodium falciparum (n=26), Plasmodium vivax (n=23), Plasmodium ovale (n=2), Plasmodium malariae (n=2), or P. vivax-falciparum (n=2), and occurred in travellers (n=24), locals (n=21), expatriates (n=6) or migrants (n=4). Median age was 31.5 years and sex ratio M/F 3.2. Splenic rupture was complete with hemoperitoneum (n=50), or partial (n=5). Death occurred in 12 patients (22%), 8 of whom from early irreversible collapse (n=7) or unexpected death (n=1). Death rate was higher among travellers than in other patients (9/24, 38%, versus 3/31, 10%, p=0.01). Clinical features of P. falciparum- or P. vivax-associated splenic rupture were strikingly similar. Treatment included in-hospital medical observation without surgery (conservative management, n=14), immediate splenectomy (n=29), delayed splenectomy (n=4), or none (patients dying at admission, n=8). The type of treatment, conservative or not, had no influence on prognosis. The median duration of malaria symptoms before diagnosis was longer in our review (5-6 days) than in previous reports on imported malaria (3-4 days), suggesting that early diagnosis and therapy of malaria may reduce the incidence of splenic rupture. CONCLUSIONS: Abdominal pain, collapse, or fainting is warning symptoms. Fourteen published observations support conservative management in carefully selected patients. Spleen preservation likely reduces the risk of future severe malaria attacks in patients with potential further exposition to Plasmodium sp., and also that of overwhelming sepsis in all.