Rational case management of malaria with a rapid diagnostic test, Paracheck Pf®, in antenatal health care in Bangui, Central African Republic.

BACKGROUND: Both treatment and prevention strategies are recommended by the World Health Organization for the control of malaria during pregnancy in tropical areas. The aim of this study was to assess use of a rapid diagnostic test for prompt management of malaria in pregnancy in Bangui, Central African Republic. METHODS: A cohort of 76 pregnant women was screened systematically for malaria with ParacheckPf® at each antenatal visit. The usefulness of the method was analysed by comparing the number of malaria episodes requiring treatment in the cohort with the number of prescriptions received by another group of pregnant women followed-up in routine antenatal care. RESULTS: In the cohort group, the proportion of positive ParacheckPf® episodes during antenatal clinics visits was 13.8%, while episodes of antimalarial prescriptions in the group which was followed-up routinely by antenatal personnel was estimated at 26.3%. Hence, the relative risk of the cohort for being prescribed an antimalarial drug was 0.53. Therefore, the attributable fraction of presumptive treatment avoided by systematic screening with ParacheckPf® was 47%. CONCLUSIONS: Use of a rapid diagnostic test is useful, affordable and easy for adequate treatment of malaria in pregnant women. More powerful studies of the usefulness of introducing the test into antenatal care are needed in all heath centres in the country and in other tropical areas.

Genetic structure of Plasmodium falciparum and elimination of malaria, Comoros archipelago.

The efficacy of malaria control and elimination on islands may depend on the intensity of new parasite inflow. On the Comoros archipelago, where falciparum malaria remains a major public health problem because of spread of drug resistance and insufficient malaria control, recent interventions for malaria elimination were planned on Moheli, 1 of 4 islands in the Comoros archipelago. To assess the relevance of such a local strategy, we performed a population genetics analysis by using multilocus microsatellite and resistance genotyping of Plasmodium falciparum sampled from each island of the archipelago. We found a contrasted population genetic structure explained by geographic isolation, human migration, malaria transmission, and drug selective pressure. Our findings suggest that malaria elimination interventions should be implemented simultaneously on the entire archipelago rather than restricted to 1 island and demonstrate the necessity for specific chemoresistance surveillance on each of the 4 Comorian islands.

Multinormal in vitro distribution model suitable for the distribution of Plasmodium falciparum chemosusceptibility to doxycycline.

The distribution and range of 50% inhibitory concentrations (IC(50)s) 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 IC(50) geometric mean ranged from 6.2 microM to 11.1 microM according to the geographical origin, with a mean of 9.3 microM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC(50) mean of 4.9 microM (+/-2.1 microM [standard deviation]); component B, with an IC(50) mean of 7.7 microM (+/-1.2 microM); and component C, with an IC(50) mean of 17.9 microM (+/-1.4 microM). 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 microM.

Rabies postexposure prophylaxis, Marseille, France, 1994-2005.

The administration of human rabies postexposure prophylaxis near Marseille (southern France) has changed since the eradication of terrestrial mammal rabies in 2001. Most injuries were associated with indigenous dogs; rabies vaccine was overprescribed. We suggest that the World Health Organization guidelines be adapted for countries free of terrestrial mammal rabies.

Rabies postexposure prophylaxis in returned injured travelers from France, Australia, and New Zealand: a retrospective study.

BACKGROUND: There is little published information available describing rabies pre- and postexposure prophylaxis (PEP) in tourists returning to their home country and seeking care for animal-associated injuries, especially those associated with a rabies risk. METHOD: We analyzed 261 travelers seeking care on returning to their home country following an animal-related injury acquired abroad. Information on individual cases of rabies (PEP) including preexposure status, type of contact with a potentially rabid animal, type of animal, and the nature of rabies PEP was collected by retrospectively analyzing records from May 1997 to May 2005. RESULTS: The majority of injuries were acquired in South-east Asia and North Africa. Only 6.8% of injured patients were previously vaccinated against rabies, while 75.4% of the cohort experienced a severe injurious contact with animals (World Health Organization category III). Of travelers who sustained a high-risk injury, only 24% received both vaccination and rabies immune globulin,(RIG) while 76% received vaccination only. Of the travelers who did not receive RIG, 43% had received a first dose of vaccine more than 7 days after return and before presenting to a clinic in their home country. CONCLUSIONS: This study highlights important deficiencies in rabies PEP for travelers who acquire high-risk, animal-associated injuries in rabies-endemic countries, with the majority not receiving adequate PEP or experiencing a substantial delay before receiving rabies vaccination.

Antimalarial drug susceptibility and point mutations associated with drug resistance in 248 Plasmodium falciparum isolates imported from Comoros to Marseille, France in 2004 2006.

A total of 248 Plasmodium falciparum isolates were sampled in travelers with malaria who came to Marseille, France from Comoros to investigate in vitro activities of antimalarial drugs and molecular markers of drug resistance. Of the 248 isolates, 126 were maintained in culture. Of these, 53% were resistant to chloroquine, and 3% had reduced susceptibility to quinine, mefloquine, and atovaquone; 1% had reduced susceptibility to halofantrine and dihydroartemisinin; 7% had reduced susceptibility to monodesethylamodiaquine; 37% had reduced susceptibility to cycloguanil; and none had reduced susceptibility to lumefantrine. Resistance-associated point mutations were screened in 207 isolates. No mutations in the cytochrome b gene were found. Of the 207 isolates, 119 (58%) had a mutation in the P. falciparum dihydrofolate reductase (Pfdhfr) gene at codon 108, 6 (5%) had mutations in both Pfdhfr codon 108 and the P. falciparum dihydropteroate synthase codon 437, and 115 (56%) had the chloroquine resistance-associated K76T mutation in the P. falciparum chloroquine resistance transporter gene. This study represents a unique opportunity to improve surveillance of P. falciparum drug resistance in Comoros with consequences for treatment and chemoprophylaxis guidelines.

Influence of oxygen on asexual blood cycle and susceptibility of Plasmodium falciparum to chloroquine: requirement of a standardized in vitro assay.

OBJECTIVE: The main objective of this study was to assess the influence of gas mixtures on in vitro Plasmodium falciparum growth and 50% inhibitory concentration (IC50) for chloroquine. METHODS: The study was performed between February 2004 and December 2005. 136 Plasmodium falciparum isolates were used to evaluate gas mixtures effect on IC50 for chloroquine by isotopic microtest. The oxygen effect on asexual blood cycle of 3D7 and W2 clones was determined by thin blood smears examination and tritiated hypoxanthine uptake. RESULTS: From 5% O2 to 21% O2 conditions, no parasiticide effect of O2 concentration was observed in vitro on the clones 3D7 and W2. A parasitostatic effect was observed during the exposure of mature trophozoïtes and schizonts at 21% O2 with an increase in the length of schizogony. The chloroquine IC50 at 10% O2 were significantly higher than those at 21% O2, means of 173.5 nM and 121.5 nM respectively (p < 0.0001). In particular of interest, among the 63 isolates that were in vitro resistant to chloroquine (IC50 > 100 nM) at 10% O2, 17 were sensitive to chloroquine (IC50 < 100 nM) at 21% O2. CONCLUSION: Based on these results, laboratories should use the same gas mixture to realize isotopic microtest. Further studies on comparison of isotopic and non-isotopic assays are needed to establish a standardized in vitro assay protocol to survey malaria drug resistance.

Pilgrims from Marseille, France, to Mecca: demographics and vaccination status.

A cohort of 461 Hajj pilgrims to Mecca departing from Marseille was surveyed. Most of travelers originated from North Africa and one third were geriatric patients. An overall low rate of vaccination was observed. The proportions of travelers without correct vaccination were 67% for influenza, 70% for tetanus, 75% for diphteria and poliomyelitis, and 87% for pertussis and hepatitis A.

Factors predictive of alcohol abstention after resident detoxication among alcoholics followed in an hospital outpatient center.

OBJECTIVES: A cohort of patient hospitalized for alcohol detoxification between January 2004 and January 2005 were followed prospectively to search for factors predictive factors of sustained abstinence. PATIENTS AND METHODS: One hundred and fifteen patients (79 males, 36 females, median age 45.9+/-10.7 years), were hospitalized for alcohol detoxification. Demographic, social, and medical data including daily alcohol intake and co-addictions were noted at inclusion and six months later. Patients who did not attend their six-month visit were contacted by phone. RESULTS: Among the 115 included patients, six month follow-up data could be collected for 73. Abstinence rate was 54.8%. Factors predictive of unsuccessful cessation were homelessness (P=0.004), duration of alcohol consumption (P=0.004), smoking (P=0.02), drug substitution (P=0.04) and multiple addictions (P=0.04). At multivariate analysis, multiple addictions was the only independent factor predictive of unsuccessful detoxification. Naltrexone or acamprosate treatments were not associated with a better rate of alcohol detoxification. CONCLUSION: Patient follow-up is problematic due to the large number of dropouts among alcoholics. Early screening in search for factors predictive of unsuccessful detoxification (long duration of alcohol consumption, multiple addiction) would be helpful in elaborating appropriate pluridisciplinary management.

Mefloquine versus 3-day oral quinine-clindamycin in uncomplicated imported falciparum malaria.

In this open randomized trial comparing 3-day oral quinine-clindamycin versus standard mefloquine regimen for uncomplicated imported falciparum malaria, mefloquine treatment was associated with a higher risk of discontinuation of the treatment (RR=1.8, 95% CI [1.1-2.8]) related to mainly mild gastrointestinal adverse drug events. The poor tolerability of mefloquine sets a question mark against its use in outpatients.

A brief review on features of falciparum malaria during pregnancy.

Malaria in pregnancy is a serious public health problem in tropical areas. Frequently, the placenta is infected by accumulation of Plasmodium falciparum-infected erythrocytes in the intervillous space. Falciparum malaria acts during pregnancy by a range of mechanisms, and chronic or repeated infection and co-infections have insidious effects. The susceptibility of pregnant women to malaria is due to both immunological and humoral changes. Until a malaria vaccine becomes available, the deleterious effects of malaria in pregnancy can be avoided by protection against infection and prompt treatment with safe, effective antimalarial agents; however, concurrent infections such as with HIV and helminths during pregnancy are jeopardizing malaria control in sub-Saharan Africa.

Fever in travelers returning from tropical areas: prospective observational study of 613 cases hospitalised in Marseilles, France, 1999-2003.

BACKGROUND: Febrile travelers may pose a diagnostic challenge for Western physicians who are frequently involved in the assessment of these patients but unfamiliar with tropical diseases. Evaluation of this situation requires an understanding of the common etiologies, which are associated with the demographics of travelers and the destinations. METHODS: We conducted a 5-year prospective observational study on the etiologies of fever in travelers returning from the tropics admitted to the infectious and tropical diseases unit of a university teaching hospital in Marseilles, France. RESULTS: A total of 613 patients were enrolled, including 364 migrants (59.4%), 126 travelers (20.6%), 37 visitors (6%), 24 expatriates (3.9%), and 62 patients (10.1%) who could not be classified. Malaria was the most common diagnosis (75.2%), with most cases (62%) acquired by migrants from the Comoros archipelago and who had traveled to these islands to visit friends and relatives. Agents of food-borne and water-borne infections (3.9%) and respiratory tract infections (3.4%) were also frequently identified as the cause of fever. Other infections included emerging diseases such as gnathostomiasis, hepatitis E infection and rickettsial diseases, as well as common infections or exotic diseases. CONCLUSIONS: Although we have identified here various causes of imported fever, 8.2% of the fevers remained unexplained. An improved approach to diagnosis may allow for the discovery of new diseases in travelers in the future.

Imported Brucellosis associated with Plasmodium falciparum malaria in a traveler returning from the tropics.

We report a microbiologically confirmed case of Brucella melitensis and Plasmodium falciparum malaria coinfection in a febrile traveler returning from Chad, Africa. The patient had been doing veterinary research in rural Chad; during that time she took no antimalarial chemoprophylaxis. Our report highlights the importance of blood cultures as well as malaria smears in febrile travelers returning from the tropics.

Severe imported malaria: clinical presentation at the time of hospital admission and outcome in 42 cases diagnosed from 1996 to 2002.

The objectives of this retrospective study were to describe initial clinical profiles and subsequent outcome of adult patients in France who were diagnosed with severe imported malaria, as defined by the World Health Organization (WHO). Forty-two patients diagnosed from 1996 to 2002 were included (median age: 30 years, men: 78%, non-immune persons: 74%, return from Africa: 100%, inappropriate antimalarial chemoprophylaxis: 95%). At the time of hospital admission, jaundice (62%), hyperparasitemia (56%), and prostration (52%) were the most frequent findings, followed by acute renal failure (31%). Other findings, as described by the WHO criteria, were less common. Twenty-three patients presented only with jaundice, hyperparasitemia, or prostration in isolation, or in combination. Of these 23, five non-immune persons subsequently developed coma, shock, acute respiratory distress syndrome or acute renal failure; this led to death in 2 of these cases. This suggests that non-immune persons with imported malaria who present with jaundice, hyperparasitemia, or prostration should be admitted to the intensive care unit for close monitoring.

Imported malaria in pregnant women: A retrospective pooled analysis.

BACKGROUND: Data on imported malaria in pregnant women are scarce. METHOD: A retrospective, descriptive study of pooled data on imported malaria in pregnancy was done using data from 1991 to 2014 from 8 different collaborators in Europe, the United States and Japan. National malaria reference centres as well as specialists on this topic were asked to search their archives for cases of imported malaria in pregnancy. A total of 631 cases were collated, providing information on Plasmodium species, region of acquisition, nationality, country of residence, reason for travel, age, gestational age, prophylactic measures and treatment used, as well as on complications and outcomes in mother and child. RESULTS: Datasets from some sources were incomplete. The predominant Plasmodium species was P. falciparum (78.5% of cases). Among the 542 cases where information on the use of chemoprophylaxis was known, 464 (85.6%) did not use chemoprophylaxis. The main reason for travelling was "visiting friends and relatives" VFR (57.8%) and overall, most cases of malaria were imported from West Africa (57.4%). Severe anaemia was the most frequent complication in the mother. Data on offspring outcome were limited, but spontaneous abortion was a frequently reported foetal outcome (n = 14). A total of 50 different variants of malaria treatment regimens were reported. CONCLUSIONS: Imported cases of malaria in pregnancy are mainly P. falciparum acquired in sub-Saharan Africa. Malaria prevention and treatment in pregnant travellers is a challenge for travel medicine due to few data on medication safety and maternal and foetal outcomes. International, collaborative efforts are needed to capture standardized data on imported malaria cases in pregnant women.

Triangular test applied to the clinical trial of azithromycin against relapses in Plasmodium vivax infections.

BACKGROUND: Sequential analysis enables repeated statistical analyses to be performed throughout a trial recruitment period, while maintaining a pre-specified power and type I error. Thus the trial can be stopped as soon as the information accumulated is considered sufficient to reach a conclusion. Sequential tests are easy to use and their statistical properties are especially suitable to trials with very straightforward objectives such as non-comparative phase II trials. We report on a phase II study based on the triangular test (TT) aiming at assessing the effectiveness of azithromycin in preventing Plasmodium vivax relapses. METHODS: To test whether the P. vivax relapse rate was either <12% or >or= 45% in patients treated with azithromycin, a sequential analysis based on the TT was as used. Patients infected with P. vivax were treated with azithromycin, 1.2 g daily, for 7 days. The onset of a relapse infection was monitored. RESULTS: Five patients presenting with an acute P. vivax infection were included in the study. All the patients were initially cured. Three patients reported mild gastrointestinal adverse effects. When the third patient relapsed, the sample path crossed the upper boundary of the TT, and the trial was stopped. CONCLUSIONS: Using the triangular test, with only a small number of patients, we concluded that azithromycin was not effective enough in preventing P. vivax relapses to warrant further evaluation in phase III. It is suggested that a wider use of sequential analysis in phase II anti-infective drugs trials may have financial and ethical benefits.

Evaluating the use of a comprehensive pretravel database by travel medicine experts and novices for advice building.

BACKGROUND: The practice of travel medicine is particularly dependent on knowledge that must be continuously updated, and that can be found in professional electronic documents (PEDs), as specialized websites or comprehensive off-line databases. In this study, we show to what extent the use of a comprehensive pretravel database can compensate for a lack of knowledge in travel medicine during advice building, despite inexperience in using such systems. METHODS: Sixteen physicians, novices and experts in travel medicine, were solicited for building adequate recommendations about real cases of international travel with the help of a specialized PED. The physician's verbalizations, browsing in the documentation and final recommendations have been analyzed for the purpose of identifying and counting the requests addressed to the system and the informative elements in the recommendations. RESULTS: Novices make 2.5 times as many requests for information as experts (p=.0009), and look for a greater variety of information, specifically connected to health precautions (p=.0012), immunizations (p=.0001), health care resources (p=.0037) and climate (p=.019), whereas experts focus their requests mainly on health risks (64.81% of requests, p5.0009). The recommendations from the two groups included equivalent quantities of about 12 pieces of information, but experts used 92.34% of the information found in the documentation, whereas novices used 72.37% (p=.00005). The most used informative elements, whatever the expertise level is, are related to immunizations and health precautions, but experts include more information about health risks (p=0.017), drug characteristics (p=0.014) and chemoprophylaxis (p=0.026). CONCLUSIONS: The PED actually increases the novices' travel medicine expertise, and is particularly efficient for immunizations and health precautions. The PED helps a novice to build advice that is, on the whole, equivalent to an expert's in terms of nature, if not of quality. Implications for the benefits of comprehensive PEDs in the practice of travel medicine are discussed.

Contribution of nonspecific laboratory test to the diagnosis of malaria in febrile travelers returning from endemic areas: value of hypocholesterolemia.

BACKGROUND: The gold standard in diagnosis of malaria is microscopic detection of malaria parasites in thin blood smears. However, the sensitivity and specificity of blood smears depend mostly on the experience of the examiner. In the traveler returning from the tropics, diagnosis of malaria may be difficult when the parasitemia is low. In this circumstance any indicator that suggests the diagnosis of malaria is of great interest. The aim of this study is to determine the value of hypocholesterolemia to the diagnosis of imported malaria. METHOD: A retrospective case-control study was performed among hospitalized patients with fever returning from a malaria-endemic area, to compare the results of routine biological parameters of 129 malaria cases with those of 92 control patients. RESULTS: Multivariate analysis, using a logistic regression model demonstrates that hypocholesterolemia was the strongest parameter associated with malaria (adjusted odds ratio [OR]: 75.22, 95% confidence interval [CI] 4.60-1227.78) and the most specific (98%, 95% CI 0.95-1.0). The most sensitive abnormality was thrombocytopenia (82%, 95% CI-0.77 0.87). With a malaria prevalence of 52% in our population study, hypocholesterolemia has the strongest positive predictive value among routine biological parameters for malaria diagnosis (96%). The combination of hypocholesterolemia and thrombocytopenia was always associated with diagnosis of malaria in this study. CONCLUSION: These results show that hypocholesterolemia is significantly associated with malaria. Therefore, in the setting of negative thin and thick blood smears, the presence of hypocholesterolemia, particularly when it is combined with thrombocytopenia, in a febrile traveler returning from a malaria-endemic area, should prompt repetition and careful analysis of blood smears to avoid misdiagnosis.