Amodiaquine dosage and tolerability for intermittent preventive treatment to prevent malaria in children.

Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child's age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.

[Comparison of PCR, ELISA-CSP and direct microscopic observation methods for the detection of Plasmodium falciparum sporozoites in Anopheles gambiae M in Senegal]. / Comparaison des méthodes de la PCR, d'ELISA-CSP et d'observation microscopique directe pour la détection des sporozoïtes de Plasmodium falciparum chez Anopheles gambiae M au Sénégal.

A comparative study between the Enzyme-Linked Immuno Sorbent Assay (ELISA-CSP) for circumsporozoitic antigen detection method, the direct observation after dissection and the polymerase chain reaction (PCR) technique used to identify Plasmodium falciparum genomic DNA markers was carried out. This to evaluate the sensibility and the specificity of the PCR, for the determination of both sporozoitic index (ICSP) and the entomological inoculation rate (EIR). The study is conducted in laboratory on eighty six specimens of Anopheles gambiae M infected after being fed with the blood of a gametocytes carrier from Dielmo (Senegal). Salivary glands of forty-eight specimens randomly selected (test A) among the infected eighty six are microscopically observed after manual dissection for the sporozoites detection. The content of these salivary glands and the crushed head/thorax of the remaining 38 specimens (test B) are tested in ELISA-CSP and PCR. The positive and negative results obtained were recorded and summarized for each method. A pair-comparison of the results obtained with each method generally revealed a good sensibility and an excellent specificity The kappa coefficient (K) of test A indicated a "moderate" to "excellent" concordance between the three different methods performed. By using the crushed head/thorax sample, generally used to determine the transmission parameters (ICSP and EIR), the PCR/ELISA-CSP concordance was excellent. In the light of the values of sensibility and specificity obtained, this PCR is comparable to the other methods for the assessment of sporozoitic index and entomological inoculation rate.

[A survey on the venomous snakes of the vicinity of Kindia (Guinea) and considerations on the treatment of snakebite]. / Etude epidémiologique des serpents venimeux et prise en charge des envenimations a Kindia (Guinée).

Between June and December 2004, snake collections were undertaken in eight villages of the vicinity of Kindia, an area of Guinea Conakry where the incidence of snakebite is among the highest reported in the world. A total of 916 specimens were collected, including 90 Elapidae (9.8 %) and 174 Viperidae (19.0%). The Black Mamba Dendroaspis polylepis was represented by eight specimens, i.e. almost 1% of the snakes collected. This species, which is considered as very rare in West Africa, appears common in this area of Guinea. The current difficulties for the treatment of snakebite due to the high increase of the cost of antivenom therapy are discussed.

[Epidemiologic evaluation of malaria in endemic areas]. / Evaluation épidémiologique du paludisme en zone d'endémie.

For decades malarial control has been implemented to control the impact of the disease on the health of populations living in endemic zones. The use of artemisinine combination therapy, intermittent preventive treatment for children and pregnant women, vector-control methods such as long-lasting insecticide-impregnated mosquito nets and indoor remanent insecticide spraying has proven to be effective. These practices have lead to such an extensive reduction of the malaria burden in some endemic areas that the objective of eradication that was unimaginable a few years ago is now back to the forefront. Regardless of the method chosen, careful evaluation and surveillance of its effectiveness in man is necessary. Achieving epidemiologic impact is the main goal of malaria control methods. The main measures for evaluation involve parasitological and clinical aspects of human malaria. The purpose of this article is to review methods used for epidemiologic evaluation of malaria burden.

Antibody responses to a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332 in Senegalese individuals naturally primed to the parasite.

Previous studies have shown that antibodies from humans exposed continuously to malaria recognize the Plasmodium falciparum asexual blood-stage antigen Pf332. Here we analysed the antibody responses to a C-terminal fragment of Pf332, designated C231, in individuals from Senegal, by measuring the serum levels of immunoglobulin M (IgM), IgG class and subclass and IgE antibodies. IgG antibody reactivity with crude P. falciparum antigen was detected in all the donors, while many of the children lacked or had low levels of such antibodies against C231. The antibody levels increased significantly with age for both crude P. falciparum antigen and C231, and in the older age groups most of the donors displayed antibodies to C231. This was also true for IgM, IgE and IgG subclass reactivity against C231. Moreover, the ratio of IgG1/IgG2 was considerably lower for C231 than for crude P. falciparum antigen, and in age groups 10-14 and 15-19 years the levels of IgG2 against C231 even exceeded that of IgG1. The IgG2/IgG3 ratios suggest that C231 gives similar levels of IgG2 and IgG3, except for children aged 4-9 years, where IgG3 was higher. Raw IgM, IgG class and subclass and IgE antibody levels to C231 tended to be higher in those who did not experience a malaria attack, but following linear multivariate analysis the trends were not significant.

Molecular divergences of the Ornithodoros sonrai soft tick species, a vector of human relapsing fever in West Africa.

The soft tick Ornithodoros sonrai is recognized as the only vector of Borrelia crocidurae causing human relapsing fever in West Africa. Its determination has been exclusively based on morphological features, geographical distribution and vector competence. Some ambiguities persist in its systematics and may cause misunderstanding about West African human relapsing fevers epidemiology. By amplifying and aligning 16S and 18S rDNA genes in O. sonrai specimens collected from 14 distinct sites in Senegal and Mauritania, we showed the existence of four genetically different subgroups that were morphologically and ecologically identified as belonging to the same species. Within O. sonrai, intraspecific polymorphism was high (pairwise divergence from 0.2% to 16.4%). In all cases, these four subgroups formed a monophyletic clade sharing a common ancestor with East African soft ticks that transmit Borrelia duttoni human relapsing fever. From amplification of the flagellin gene of B. crocidurae we verified that all subgroups of O. sonrai were infected by B. crocidurae and may constitute vectors for this pathogen. All flagellin sequences were identical, refuting the hypothesis suggesting parallel evolution between O. sonrai and B. crocidurae. However, differences in infection rates were significant, suggesting different vector competences between subgroups of O. sonrai.

Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial.

BACKGROUND: It is recommended that children aged 3 months to five years of age living in areas of seasonal transmission in the sub-Sahel should receive Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) during the malaria transmission season. The purpose of this study was to evaluate the safety of SMC with SPAQ in children when delivered by community health workers in three districts in Senegal where SMC was introduced over three years, in children from 3 months of age to five years of age in the first year, then in children up to 10 years of age. METHODS: A surveillance system was established to record all deaths and all malaria cases diagnosed at health facilities and a pharmacovigilance system was established to detect adverse drug reactions. Health posts were randomized to introduce SMC in a stepped wedge design. SMC with SPAQ was administered once per month from September to November, by nine health-posts in 2008, by 27 in 2009 and by 45 in 2010. RESULTS: After three years, 780,000 documented courses of SMC had been administered. High coverage was achieved. No serious adverse events attributable to the intervention were detected, despite a high level of surveillance. CONCLUSIONS: SMC is being implemented in countries of the sub-Sahel for children under 5 years of age, but in some areas the age distribution of cases of malaria may justify extending this age limit, as has been done in Senegal. Our results show that SMC is well tolerated in children under five and in older children. However, pharmacovigilance should be maintained where SMC is implemented and provision for strengthening national pharmacovigilance systems should be included in plans for SMC implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00712374.

Correction: Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial.

[This corrects the article DOI: 10.1371/journal.pone.0162563.].

[Evaluating malaria attributable morbidity in endemic areas]. / Comment évaluer la morbidité attribuable au paludisme en zone d'endémie?

There are no specific clinical signs or symptoms of malaria. Fever attacks, anemia, or signs of severity like coma or respiratory distress cannot easily be attributed to malaria in people who are infected most of the time. Ascribing clinical manifestations to malaria is problematic in populations that are regularly exposed to the transmission of human plasmodia. The more transmission is intense and regular, the higher the prevalence of asymptomatic infections. In areas of intense and perennial malaria transmission, more than 90% of the population may be infected and the simple detection of a plasmodial infection is not enough to attribute clinical manifestations to malaria. Naturally acquired anti-malaria immunity permitting asymptomatic infections is incomplete and temporary. It is an obstacle to the estimation of the malaria burden in endemic areas. The positive association between parasite density and fever allows the attribution of clinical attacks to malaria. The relationship between parasitaemia and the risk of fever is not continuous. An age- and endemicity-dependent threshold effect of parasite density has been demonstrated and can be used to distinguish clinical attacks due to malaria from others. Clinical diagnosis and evaluation of malaria are problematic in three situations: in public health to estimate the malaria burden for health services, in clinical research to evaluate treatments or prophylactic measures (drug, vaccine, anti-vectorial devices), and in basic research on pathophysiology, immunology or genetic susceptibility to clinical malaria. No one diagnostic definition nor procedure for detecting cases is adequate for all three purposes. Case detection may be passive (in health structures for example) or active (in population). The choice of methods for diagnosis and recruitment depends on the objectives and whether a "pragmatic" or "explicative" approach is used. The radical differences between these approaches are often unsuspected or ignored.

[The incidence of snakebite in a rural zone of southeastern Senegal]. / L'incidence des morsures de serpent en zone rurale au Sénégal oriental.

In order to complete an exploratory study on the risk of death due to snakebite in a rural zone of South-Eastern Senegal, we have carried out a survey to estimate the incidence of snakebites in the same population. The study made on a sample of almost 600 subjects showed an annual incidence of 677 bites per 100.000 inhabitants, that is one of the most important rate ever reported in the world until now. Based on these results and data collected previously on deaths due to snakebites in this same population, we provide an estimate of snakebite case fatality rate of 2.1% in this area of Senegal.

[Changes in malaria prevalence and management of fevers from 2000 to 2012 in Casamance, Senegal]. / Évolution de la prévalence du paludisme et de la prise en charge des fièvres de 2000 et 2012 en Casamance, Sénégal.

Before 2006 in Senegal, in the absence of clinical diagnosis, all fever cases were considered as malaria and treated with chloroquine. Between 2004-2006, to face the dramatic increase of Plasmodium falciparum resistance to chloroquine, the combination of amodiaquine plus sulfadoxine-pyriméthamine was recommended for treatment. In 2006, rapid diagnostic tests were introduced and the treatment with a combination of artesunate plus amodiaquine (ASAQ) became the national recommendation for malaria treatment in 2007. This coincided with a decrease of the prevalence of malaria cases and change in fever management. Since 1995 in Mlomp in Casamance, thin and thick blood smear examination has systematically been done in patients with fever and clinical signs of malaria, and treatment with ASAQ given as experimental procedure. Between 2000 and 2012, 70,892 outpatients were attending the health center, and 51.2% of them for fever. Among these fever cases, 72.4% were suspected of malaria and 27.6% were identified as bacterial and viral infections. Confirmed malaria cases decreased dramatically from 1365 in 2000 to 53 in 2012. While comparing the 2 periods 2000-2006 and 2007-2012, the number of fever cases decreased by half, the number of fever identified as non malaria doubled and malaria treatment given decreased by 86%. Improvement of fever management in Mlomp has contributed to a better identification of their cause and to a decrease of inappropriate malaria treatments.

The past, present and future of childhood malaria mortality in Africa.

During the past few years, there has been a historic series of declarations of renewed commitment to malaria control in Africa. Whether the burden of malaria is increasing in Africa is a moot point. This article attempts to re-construct the evidence for the trends in childhood mortality as a result of Plasmodium falciparum infection over the last century in Africa.

Rapid decline in child mortality in a rural area of Senegal.

Retrospective and prospective demographic and health data collected on the population of Mlomp (6352 people in 1985), a rural area of Senegal, show that the probability of dying before the age of 5 years declined from 350 to 81 deaths per hundred livebirths in the last 25 years. This decline is greater and faster than ever observed in Senegal. The drop in mortality mainly results from improved access to new and efficient health services--a dispensary and a maternity clinic--and from growth surveillance, health education, vaccination and malaria programmes initiated in the 1960s and 1970s. Although socioeconomic conditions have changed in the area, the influence of classical factors such as women's educational level and improvement in transportation has probably been limited. Deaths from diseases that can be prevented by immunization (such as neonatal tetanus, measles, whooping cough) are now very rare (3% of the deaths of children under 5 years during the period 1985-1989). Although the risks of dying from diarrhoea or acute respiratory infections are much lower than in other rural areas of Senegal, these are still the main causes of deaths (33% and 19% of deaths after 1 month of age). Malaria, despite its high morbidity during the rainy season, causes few deaths (4%). This reflects the success of the health education programme promoting chemoprophylaxis and early treatment of fever cases. Mlomp is one example of an African rural area where the provision of well-organized health services at a reasonable cost has produced a dramatic decline in child mortality.

The public health impact of chloroquine resistance in Africa.

Between 1978 and 1988 Plasmodium falciparum resistance to chloroquine has been reported in all countries of tropical Africa. Despite the intensification of resistance during the last 2 decades, chloroquine remains in 2000 the first-line treatment for malaria in most of these countries. Here we review published data on the public health impact of antimalarial drug resistance in Africa. These data show that since the late 1980s convincing evidence of a major public health impact of the spread of chloroquine resistance has been available. Hospital studies in various African countries have documented a 2- or 3-fold increase in malaria deaths and admissions for severe malaria, an increase temporally related to the emergence of chloroquine resistance. Data from sentinel demographic surveillance systems in Senegal indicated that mortality attributable to malaria in children increased by as much as 6-fold among populations where low levels of malaria mortality had been achieved because of efficient health services before the emergence of chloroquine resistance. Increasing incidence of severe malarial anemia also contributed to human immunodeficiency virus dissemination. The dramatic impact of chloroquine resistance on malaria mortality has long been underestimated because only a low proportion of malaria attacks are potentially lethal among persons continuously exposed since birth to high levels of transmission. There is an urgent need to change treatment policies in Africa.

Evidence for an age-dependent pyrogenic threshold of Plasmodium falciparum parasitemia in highly endemic populations.

The high prevalence of asymptomatic malaria infections and the nonspecific signs and symptoms of the disease make the individual diagnosis of clinical malaria uncertain in highly endemic areas. Longitudinal data obtained during a four-month period from a daily survey of 200 permanent inhabitants (one month-83 years old) living in a holoendemic area were analyzed in a random-effects logistic regression model to investigate the relationship between the level of Plasmodium falciparum parasitemia and risk of fever. It was not possible to build a model that described/summarized correctly this relationship by a continuous function. Findings provide evidence for an age-dependent threshold effect of parasitemia on the occurrence of fever. The level of this threshold varied by 2.45 trophozoites per leukocyte, maximum at one year of age, to 0.5 trophozoites per leukocyte, minimum at 60 years of age. When the parasite density of a person crossed the threshold level corresponding to his or her age, the individual's risk of fever was multiplied by 44 (95% confidence interval = 13.6-144.8). The existence of this threshold effect allows parasite density to be used to distinguish malaria attacks from other causes of fever within an individual and should facilitate the accurate evaluation of the incidence of clinical malaria in highly endemic areas.

Short report: gametocytes, chloroquine pressure, and the relative parasite survival advantage of resistant strains of falciparum malaria in west Africa.

Patients with Plasmodium falciparum infections were selected with an in vivo chloroquine sensitivity assay. Fourteen days after treatment, the gametocytes were studied in relation to asexual parasite responses classified as drug-sensitive or showing RI or RII resistance. Gametocyte prevalence and density appeared significantly higher in RII than RI strains and higher in RI than in sensitive strains. This finding on gametocyte variation in vivo may explain why the RII type of chloroquine resistance has became more prevalent than RI everywhere in tropical Africa in the short time since its emergence. The biological and epidemiologic advantage of chloroquine-resistant malaria mediated through gametocytes is discussed in the context of the present drug pressure in Africa.

Rapid reappearance of Plasmodium falciparum after drug treatment among Senegalese adults exposed to moderate seasonal transmission.

To investigate the relationship between the entomologic inoculation rate (EIR) and time to reappearance of malaria parasites after radical treatment under moderate seasonal transmission conditions, a study was undertaken in a mesoendemic area of Senegal where malaria transmission is concentrated over an annual three-month period and averages 12 infective bites per person per year. A three-day course of quinine was administered to 48 asymptomatic adults between 19 and 66 years of age. Malaria transmission and parasitemia were monitored every week for two months and cases of fever or symptoms were investigated as part of a daily clinical surveillance. The proportion of persons reinfected at Days 28, 35, and 56 was 25%, 38%, and 54%, respectively. Adults less than 40 years of age had a shorter time to reinfection. In this age group, the median Plasmodium falciparum reappearance time was 28 days, and it was estimated that only one infected mosquito bite was able to induce a patent infection among half of the subjects. Only 8% (2 of 26) of the reinfections caused a clinical attack. These data are discussed in the light of previous studies conducted among adults naturally exposed to intense perennial transmission or among naive volunteers receiving artificial challenges. Rapid reinfection occurs at very low EIRs and dramatic differences in actual and cumulated exposure to infected mosquito bites poorly affect the median time to reappearance of malaria parasites in endemic populations.

A longitudinal survey of Borrelia crocidurae prevalence in rodents and insectivores in Senegal.

We report results of a longitudinal survey designed to determine the importance and the dynamics of Borrelia crocidurae, the spirochete responsible for tick-borne relapsing fever in West Africa in rodents and insectivores in a rural area of northern Senegal. A total of 954 animals were caught during bimonthly capture sessions over a two-year period. Positive thick blood smears were recorded in 17.6% of the 740 rodents and 7.3% of the 55 musk shrews tested. Variations of prevalence were analyzed in Arvicanthis niloticus and Mastomys huberti, which represented 62.7% and 28.3%, respectively. of the animals captured, and 65.7% and 27.6%, respectively, of the animals found infected. Borrelia crocidurae prevalence was significantly different between captures and fluctuated separately for each species. Age-specific prevalence of B. crocidurae showed distinct patterns, decreasing with age from 50% in younger juveniles to 3% in older adults for A. niloticus, while increasing with age from 8% to 23% for M. huberti. No relationship was observed with animal abundance or with the season of the year for either species. These findings suggest that the diversity of the population dynamics of host-vector-parasite associations in the Sahel region of Senegal may be a key factor for the relative stability of the borreliosis reservoir.

Host factors affecting the delay of reappearance of Plasmodium falciparum after radical treatment among a semi-immune population exposed to intense perennial transmission.

To investigate host factors affecting the delay of reappearance of malaria parasites after radical treatment, a study was undertaken in Dielmo, Senegal, an area of intense perennial malaria transmission. A 7-day course of quinine was administered to 173 asymptomatic persons from 1 to 85 years of age and reappearance of malaria parasites in the peripheral blood was monitored weekly for 14 weeks. Additional thick blood films were made in case of fever as part of a daily clinical surveillance. The median times before reappearance of Plasmodium falciparum were 22, 39, and 53 days among persons 1-6, 7-14, and > or = 15 years of age, respectively (P < 0.0001). Multivariate analysis indicated that the daily rate of reappearance of P. falciparum was 2.2 (95% confidence interval [CI] = 1.2-4.5) times lower in sickle cell trait carriers than in AA individuals, and 1.5 (95% CI = 1.1-2.1) times lower in bed nets users than in non-users. The risk ratio for the daily risk of reappearance was significantly related to the level of parasitemia before treatment. No influence of glucose-6-phosphate dehydrogenase deficiency, HLA-B53, and DR13 were observed. Findings show that monitoring during a few weeks the reappearance of malaria parasites after treatment among a small cohort of individuals naturally exposed to malaria is relevant for investigating host resistance factors. This suggest that small, low-cost, field trials may be very informative on the potential of new malaria vaccine candidates.

Vector density gradients and the epidemiology of urban malaria in Dakar, Senegal.

The dispersion of anopheline mosquitoes from their breeding places and its impact on malaria epidemiology has been investigated in Dakar, Senegal, where malaria is hypoendemic and almost exclusively transmitted by Anopheles arabiensis. Pyrethrum spray collections were carried out along a 910-meter area starting from a district bordering on a permanent marsh and continuing into the center of the city. According to the distance from the marsh, vector density (the number of An. arabiensis per 100 rooms) at 0-160, 160-285, 285-410, 410-535, 535-660, 660-785, and 785-910 meters was 84, 40, 5, 2, 2, 0.4, and 0, respectively, during the dry season, and 414, 229, 110, 84, 99, 69, and 21, respectively, during the rainy season. The proportion of 8-11-year-old children with negative immunofluorescent antibody test results for Plasmodium falciparum was 17%, 28%, 44%, 54%, 50%, 63%, and 73%, respectively, in these different sections. Malaria prevalence in the community was maximum in the area bordering on the marsh where it ranged from 1% to 15% (average 6%) according to age and season of the year. These findings show the epidemiologic importance of vector density gradients in Dakar. The implications for malaria control in urban areas are discussed.