Intravenous Artesunate for the Treatment of Severe Imported Malaria: Implementation, Efficacy, and Safety in 1391 Patients.

BACKGROUND: Intravenous artesunate is the World Health Organization-recommended first-line treatment for severe malaria worldwide, but it is still not fully licensed in Europe. Observational studies documenting its safety and efficacy in imported malaria are thus essential. METHODS: We prospectively collected clinical and epidemiological features of 1391 artesunate-treated patients among 110 participant centers during the first 7 years (2011-2017) of a national program implemented by the French Drug Agency. RESULTS: Artesunate became the most frequent treatment for severe malaria in France, rising from 9.9% in 2011 to 71.4% in 2017. Mortality was estimated at 4.1%. Treatment failure was recorded in 27 patients, but mutations in the Kelch-13 gene were not observed. Main reported adverse events (AEs) were anemia (136 cases), cardiac events (24, including 20 episodes of conduction disorders and/or arrhythmia), and liver enzyme elevation (23). Mortality and AEs were similar in the general population and in people with human immunodeficiency virus, who were overweight, or were pregnant, but the only pregnant woman treated in the first trimester experimented a hemorrhagic miscarriage. The incidence of post-artesunate-delayed hemolysis (PADH) was 42.8% when specifically assessed in a 98-patient subgroup, but was not associated with fatal outcomes or sequelae. PADH was twice as frequent in patients of European compared with African origin. CONCLUSIONS: Artesunate was rapidly deployed and displayed a robust clinical benefit in patients with severe imported malaria, despite a high frequency of mild to moderate PADH. Further explorations in the context of importation should assess outcomes during the first trimester of pregnancy and collect rare but potentially severe cardiac AEs.

Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins.

Patients with severe malaria treated with artesunate sometimes experience a delayed hemolytic episode. Artesunate (AS) induces pitting, a splenic process whereby dead parasites are expelled from their host erythrocytes. These once-infected erythrocytes then return to the circulation. We analyzed hematologic parameters in 123 travelers treated with AS for severe malaria. Among 60 nontransfused patients observed for more than 8 days, 13 (22%) had delayed hemolysis. The peak concentration of circulating once-infected erythrocytes was measured during the first week in 21 patients and was significantly higher in 9 patients with delayed hemolysis than in 12 with other patterns of anemia (0.30 vs 0.07; P = .0001). The threshold of 180 million once-infected erythrocytes per liter discriminated patients with delayed hemolysis with 89% sensitivity and 83% specificity. Once-infected erythrocyte morphology analyzed by using ImageStream in 4 patients showed an 8.9% reduction in their projected area, an alteration likely contributing to their shorter lifespan. Delayed clearance of infected erythrocytes spared by pitting during AS treatment is an original mechanism of hemolytic anemia. Our findings consolidate a disease framework for posttreatment anemia in malaria in which delayed hemolysis is a new entity. The early concentration of once-infected erythrocytes is a solid candidate marker to predict post-AS delayed hemolysis.

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.

Predictors of Outcome after Direct Aspiration of Basilar Artery Occlusion.

Background: Basilar artery occlusion (BAO) is a serious disease with a poor prognosis if left untreated. Endovascular therapy (EVT) is the most effective treatment that is able to reduce mortality and disability. Treatment results are influenced by a wide range of factors that have not been clearly identified. In the present study, direct aspiration was chosen as a first-line treatment. The safety and effectiveness of direct aspiration in BAO were determined, and factors affecting patient outcomes were identified. Methodology: Data for patients with BAO treated between November 2013 and December 2021 were evaluated using a database. The association between clinical and procedural parameters and functional outcome was assessed. Results: A total of 89 patients with BAO were identified. Full recanalization was achieved in 69.7% of cases and partial recanalization in 19.1%. Intracranial hemorrhage was detected in 11 (12.4%) patients, of which, eight (9.0%) patients experienced symptomatic intracranial hemorrhage. Patients with good outcomes presented with milder strokes (mean NIHSS score of 12.58 vs. 24.00, p < 0.001), had higher collateral scores (6.79 vs. 5.88, p = 0.016), more often achieved complete recanalization (87.9% vs. 58.9%, p = 0.009), and more often experienced early neurological improvement (66.7% vs. 26.8%, p < 0.001). On the contrary, patients with worse outcomes had higher serum glucose levels (p = 0.05), occlusion of the middle portion of the basilar artery (MAB) (30.3% vs. 53.6%, p = 0.033), longer thrombus lengths (10.51 vs. 16.48 mm, p = 0.046), and intracranial hemorrhage (p = 0.035). Conclusions: The present study results suggest that direct aspiration is a safe and effective treatment for patients with BAO. We identified several factors affecting the patients' outcome.

Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000-2011.

BACKGROUND: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system. METHODS: The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers' isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates. RESULTS: A total of 2874 parasite isolates were genotyped between 2000-2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = -0.3, p < 10-3). CONCLUSIONS: An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011 and they correlated to the decrease of the drug pressure.

[Imported severe falciparum malaria in France in 2000-2011: epidemiological trends and the need for new treatments]. / Le paludisme grave a P. falciparum en France, 2000- 2011: evolution epidémiologique et nécessité d'une nouvelle prise en charge thérapeutique.

In France malaria is monitored by the Centre National de Référence (CNR) du Paludisme (French National Malaria Reference Centre). The annual incidence of imported malaria currently ranges from 4 800 to 3 500 cases and has fallen gradually since 2000. However, the proportion of patients with severe P. falciparum malaria is increasing (2.5% in 2000, 7% in 2011), particularly among French residents from sub-Saharan Africa who neglect preventive measures. Overall mortality remains stable at 0.4%, but survival is improving in severe cases. The survival rate is higher among patients of African origin than among Europeans. Nonetheless, between 10 and 20 patients die of malaria every year in France. Two large controlled trials published in 2005 and 2010 showed that IV artesunate, a new treatment for severe falciparum malaria, is associated with a 22-38% absolute reduction in mortality relative to quinine. Artesunate is not licensed in Europe but has been available in France since May 2011 through a named-patient program controlled by the French Agency for Drug Safety [ANSM]. The first 99 patients treated with artesunate up to September 2012 experienced satisfactory efficacy and tolerability. Delayed, sometimes persistent anemia was observed in 13 patients, a rate similar to that noted in recent reports on imported malaria in Europe. This unexpected adverse effect requires further investigation. IV artesunate is now recommended as the first-line treatment for severe falciparum malaria in France.

[Malaria today]. / Le paludisme aujourd'hui.

Malaria, a parasitic disease the pathogen of which was discovered by Alphonse Laveran in 1880 in the blood of febrile patients, remains in 2022 the most frequent endemic disease in tropical and subtropical countries. In its latest "World Malaria Report" available in November 2021, the WHO deals in great detail with the data collected in the field in 2019-2020, their progression over the last 20 years, and the measures to be taken to try to better control this life-threatening endemic. The number of malaria cases is estimated at 232 million in 2019 in 87 endemic countries, down from 245 million in 2000. The WHO African Region alone accounts for 94% of cases and the most frequent and severe infections due to Plasmodium falciparum species. If children under the age of 5 are not treated promptly, they can die. Globally, the number of malaria deaths declined steadily over the period 2000-2019, from 897,000 in 2000 to 568,000 in 2019, with nearly 95% of deaths occurring in 31 countries, primarily in sub-Saharan Africa. In other WHO regions, including Southeast Asia, malaria deaths decreased by 74%, with 35,000 deaths in 2000 compared to 9,000 in 2019. Malaria can be controlled worldwide, and possibly eradicated, if public information campaigns are strengthened and sufficient funds are made available.

Larva Currens: Report of Seven Cases and Literature Review.

Strongyloidiasis is a frequent and often unrecognized parasitic disease because of the frequently asymptomatic nature and lack of sensitivity of diagnostic tests. Under conditions of immunosuppression (particularly systemic corticosteroid treatment), potentially fatal dissemination may occur. Thus, prevention and early diagnosis are important. Larva currens is a rare and pathognomonic cutaneous sign of strongyloidiasis, but is poorly described because of its unpredictable and fleeting occurrence. We report seven imported cases of larva currens seen in Paris between 1990 and 2020. We illustrate the clinical and biological features of this specific but uncommon sign of strongyloidiasis with clinical pictures. There were three males and four females, aged between 29 and 58 years. There were five migrants from endemic countries, one tourist and one expatriate. Digestive disorders were the main extracutaneous signs. All patients had eosinophilia above 0.5 G/L. All cases were confirmed by stool tests. All were cured with ivermectin. The rapidity and the short duration of the creeping eruption distinguish it from other parasitoses. Ivermectin is a treatment of choice. The key point is to think about preventing disseminated strongyloidiasis before giving corticosteroids not only among migrants but also among expatriates and tourists in endemic countries.

A brief history of malaria.

For millions of years, invertebrates and malaria parasites have coexisted and to date, malaria remains the most important human parasitic disease. This co-evolution had profound impacts on the movements of early hominids and on the genome of modern humans. Over the past two centuries, progress has been made with the discovery of the parasite, its transmission, and medicines, paving the way to the control of the disease and its elimination in some countries. However, the Plasmodium parasite is a formidable foe capable of developing resistance to drugs, and the mosquito vector has adapted to insecticides, foiling all attempts to eradicate the disease. Over recent years the economic and social costs of malaria have been recognized and more funds have been mobilized than ever before, however further efforts are needed. National programs, international institutions and researchers will need to do better if the preventable deaths of hundreds of thousands of mostly African children are to be averted.

Superiority of 3 over 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria during pregnancy in mali: a randomized controlled trial.

BACKGROUND: In 2003, Mali introduced intermittent preventive therapy in pregnancy (ITPp) with sulfadoxine-pyrimethamine (SP) for the control of malaria in pregnancy, consisting of 2 doses of SP given in the 2nd and 3rd trimester. This widely used regimen, although very effective, leaves many women unprotected from malaria during the last 4-to-8 weeks of gestation, which is a pivotal period for fetal weight gain. The aim of the study was to compare the efficacy and safety of 3-dose versus 2-dose IPTp-SP for the prevention of placental malaria and associated low birth weight (LBW). METHODS: We conducted a parallel-group, open-label, individually randomized controlled superiority trial involving 814 women of all gravidity, enrolled from April 2006 through March 2008. All women were seen at least 3 times and received either 2 (n = 401) or 3 (n = 413) doses of IPTp-SP. The primary endpoint measured was placental malaria, LBW, preterm births, and maternal anemia were secondary endpoints, and severe maternal skin reactions and neonatal jaundice were safety endpoints. RESULTS: Among the 96% of study subjects who were followed up until delivery, the prevalence of placental malaria was 2-fold lower in the 3-dose group (8.0%) than in the 2-dose group (16.7%); the adjusted prevalence ratio (APR) was 0.48 (95% confidence interval [CI], 0.32-0.71). LBW and preterm births were also reduced; the prevalence of LBW was 6.6% in the 3-dose group versus 13.3% in the 2-dose group (APR, 0.50; 95% CI, 0.32-0.79), and the prevalence of preterm births was 3.2% versus 8.9% (APR, 0.37; 95% CI, 0.19-0.71). No significant reductions in maternal anemia or differences in safety endpoints were observed. CONCLUSIONS: Adding a third dose of ITPp-SP halved the risk of placental malaria, LBW, and preterm births in all gravidae, compared with the standard 2-dose regimen, in this area of highly seasonal transmission with low levels of SP resistance. CLINICAL TRIALS REGISTRATION: ISRCTN 74189211.

Severe imported Plasmodium falciparum malaria, France, 1996-2003.

Little is known about severe imported Plasmodium falciparum malaria in industrialized countries where the disease is not endemic because most studies have been case reports or have included <200 patients. To identify factors independently associated with the severity of P. falciparum, we conducted a retrospective study using surveillance data obtained from 21,888 P. falciparum patients in France during 1996-2003; 832 were classified as having severe malaria. The global case-fatality rate was 0.4% and the rate of severe malaria was ≈3.8%. Factors independently associated with severe imported P. falciparum malaria were older age, European origin, travel to eastern Africa, absence of chemoprophylaxis, initial visit to a general practitioner, time to diagnosis of 4 to 12 days, and diagnosis during the fall-winter season. Pretravel advice should take into account these factors and promote the use of antimalarial chemoprophylaxis for every traveler, with a particular focus on nonimmune travelers and elderly persons.

Pooling aqueous humor samples: bias in 2D-LC-MS/MS strategy?

The proteomic analysis of body fluids presents a major challenge in studies of human diseases. Traditional techniques for protein separation require large volumes and large amounts of protein, which may be difficult to obtain for certain fluids, such as the aqueous humor (AH). Two-dimensional liquid chromatography (2D-LC-MS/MS), adapted for peptides separation from complex protein mixtures, provides an alternative approach in proteomic analysis with a potential utility in biomarker research. We investigated several different 2D-LC-MS/MS methods for use with the AH of patients with cataract, traditionally used as a control group in studies of ocular diseases. We compared analyses of individual samples with analyses of pools of proteins or peptides, and found that the investigation strategy used strongly influenced protein identification. We identified 71 proteins related to extracellular proteins highly abundant in serum (e.g., albumin or transferrin) and involved in various functions, such as transport and metabolism, together with intracellular (myeloblastin) or organelle-specific proteins (cytochrome c). An evaluation of the advantages and disadvantages of each method suggested that individual analyses and the use of peptide mixtures should be favored as complementary techniques in the search for biomarkers in ocular diseases.

Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base.

BACKGROUND: Halofantrine (HF) was considered an effective and safe treatment for multi-drug resistant falciparum malaria until 1993, when the first case of drug-associated death was reported. Since then, numerous studies have confirmed cardiac arrythmias, possibly fatal, in both adults and children. The aim of the study was to review fatal HF related cardiotoxicity. METHODS: In addition, to a systematic review of the literature, the authors have had access to the global safety database on possible HF related cardiotoxicity provided by GlaxoSmithKline. RESULTS: Thirty-five cases of fatal cardiotoxicity related to HF, including five children, were identified. Females (70%) and patients from developing countries (71%) were over-represented in this series. Seventy-four percent of the fatal events occurred within 24 hours of initial exposure to HF. Twenty six patients (74%) had at least one predisposing factor for severe cardiotoxicity, e.g., underlying cardiac disease, higher than recommended doses, or presence of a concomitant QT-lengthening drug. All (100%) of the paediatric cases had either a contraindication to HF or an improper dose was given. In six cases there was no malaria. CONCLUSION: A distinction should be made between common but asymptomatic QT-interval prolongation and the much less common ventricular arrhythmias, such as torsades de pointes, which can be fatal and seem to occur in a very limited number of patients. The majority of reported cardiac events occurred either in patients with predisposing factors or with an improper dose.Therefore, in the rare situations in which HF is the only therapeutic option, it can still be given after carefully checking for contraindications, such as underlying cardiac disease, bradycardia, metabolic disorders, personal or family history of long QT-interval or concomitant use of another QT-prolonging drug (e.g., mefloquine), especially in females.

Intermittent preventive antimalarial treatment to children (IPTc): firebreak or fire trap?

Intermittent preventive treatment is the prescheduled administration of antimalarial drugs to at-risk patients in endemic areas. This approach, which is recommended for pregnant women, is being evaluated in children. Sulfadoxine-pyrimethamine plus amodiaquine recently proved to be more protective than artemisinin-containing regimens. Therefore, the use of artemisinin derivatives could potentially be restricted to symptomatic patients. Determinants of three pending issues: safety, efficacy throughout childhood, and effectiveness--the latter depending on the implementation of sustainable delivery mechanisms--are analyzed in this comment.

Chagas disease, France.

Chagas disease (CD) is endemic to Latin America; its prevalence is highest in Bolivia. CD is sometimes seen in the United States and Canada among migrants from Latin America, whereas it is rare in Europe. We report 9 cases of imported CD in France from 2004 to 2006.

Spectrum of dermatoses in 165 travelers returning from the tropics with skin diseases.

The spectrum of dermatoses occurring in travelers returning from tropical areas is poorly documented. We analyzed the relative frequency of travel-associated dermatoses and their possible relationships to travel characteristics in all persons who came to our hospital between November 2002 and May 2003 for a cutaneous disorder related to travel in a tropical country. One hundred sixty-five travelers were included. The main dermatoses identified were infectious cellulitis (12.7%), scabies (10.3%), and pruritus of unknown origin (PUO) (9.1%). Tropical dermatoses accounted for 33.9% of the cutaneous disorders. Univariate analysis showed statistically significant correlations of infectious cellulitis with females, PUO with older age and immigrant status, pyoderma with expatriate status, scabies with tourism and travel to Africa, myiasis with tourism and travel to Africa and America, filariasis with travel to Africa and immigrant status, and cutaneous larva migrans with tourism. Dermatoses diagnosed in travelers returning from the tropics seemed to be influenced by traveler status and region visited.

Acute neuroschistosomiasis: two cases associated with cerebral vasculitis.

Encephalitis and focal neurologic deficits can occur during the acute phase of schistosomiasis. We report two cases in which cerebral imaging showed cerebral vasculitis located in arterial junctional territories. These neurologic complications may be caused by eosinophil-mediated toxicity. Immediate treatment should consist of corticosteroids rather than specific antischistosomal drugs, which may aggravate the disorders.