Malaria in France: Mainland and territories

Malaria, which was eliminated first from Metropolitan France (mainland and Corsica), then in the French West Indies and the Reunion Island during the 20^th century, remains endemic in two French territories: French Guiana and the Indian Ocean Mayotte island. Despite differences in the dominating plasmodial species and epidemiological patterns, these two territories have achieved marked quantitative improvements (in the reported number of cases and severe cases) thanks to efforts undertaken over the past decade. The situation, however, remains a concern from a qualitative standpoint with the emergence of resistance to antimalarial drugs and logistical and administrative issues which hinder access to treatment. Although malaria was eradicated in Metropolitan France half a century ago, competent vectors remain present in part or all of these territories and can give rise to limited outbreaks.     

Malaria co-infection in children influences antibody response to schistosome antigens and inflammatory markers associated with morbidity

The epidemiological coexistence of schistosomiasis and malaria is frequently observed in developing countries. Co-infection with malaria in children could influence the development of acquired immunity associated with the resistance or the pathology of schistosomiasis. In the present study, performed during May to June 1996 in Senegal, the humoral immune response to Schistosoma haematobium 28 kDa glutathione S-transferase (Sh28GST) vaccinal antigen and to soluble egg antigens (SEA) has been evaluated in individuals infected by S. haematobium. Specific immunoglobulin G3 (IgG3) and IgE responses were significantly higher in co-infected children with Plasmodium falciparum compared with children infected with S. haematobium only. In addition, circulating levels of interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and soluble tumor necrosis factor receptor II (sTNF-RII), 3 parameters associated with schistosomiasis morbidity, were significantly increased in co-infected children. Taken together, this study indicated that malaria co-infection can both influence the acquired specific immune response to schistosome antigens and unbalance the regulation of inflammatory factors closely involved in schistosomiasis pathology.     

Malaria prevalence and morbidity among children reporting at health facilities in Nouakchott, Mauritania

Although malaria has become a serious public health problem in Mauritania since the late 1990s, few documented data on its epidemiology exist. The objective of this study was to assess the morbidity of clinical malaria among children in Nouakchott. Three hundred and one febrile children, consulting at three health facilities of Nouakchott, were screened for malaria in 2009 (n=216) and 2010 (n=85). Plasmodium species identification and parasite density were determined by microscopic examination of Giemsa-stained thin and thick films and confirmed by rapid diagnostic test and nested PCR. Of 301 febrile children, 105 (34.9%) were malaria-positive by nested PCR and 87 (28.9%) by microscopy. Plasmodium vivax represented 97.1% (102/105) and P. falciparum accounted for 2.9% (3/105) of positive cases. All positive children under five years old were infected with P. vivax. The highest numbers of malaria positives were found during or shortly after the rainy season and the lowest during the dry season. Fifty-four of 105 (51.4%) malaria cases, all with P. vivax, had never travelled outside Nouakchott. Individuals belonging to the Moors ethnic group represented 97.0% of P. vivax cases. Results of the present study indicate that malaria is endemic in Nouakchott and that P. vivax is the principal causative agent. Regular surveillance is required to monitor malaria prevalence and incidence, and further measures are needed to counter the possible spread of malaria in the country.     

The IC50 of anti-Pfs25 antibody in membrane-feeding assay varies among species

Plasmodium falciparum surface protein 25 (Pfs25) is a candidate for transmission-blocking vaccines (TBVs). Anti-Pfs25 antibodies block the development of oocysts in membrane-feeding assays and we have shown the activity correlates with antibody titer. In this study, we purified Pfs25-specific IgGs to convert antibody titer to μg/mL and determined the amount of antibody required to inhibit 50% of oocyst development (IC₅₀). The IC₅₀ were, 15.9, 4.2, 41.2, and 85.6 μg/mL for mouse, rabbit, monkey and human, respectively, and the differences among species were significant. Anti-Pfs25 sera from rabbit, monkey and human showed different patterns of competition against 6 mouse monoclonal antibodies, and the avidity of antibodies among four species were also different. These data suggests that information obtained from animal studies which assess efficacy of TBV candidates may be difficult to translate to human immunization.     

New use of primaquine for malaria

Primaquine is the only available drug to treat Plasmodium vivax liver stages (hypnozoites). It has been used for more than five decades and is now included in an increasing number of clinical guidelines. The major concern is induced hemolysis when administered to glucose-6-phosphate-dehydrogenase deficient patients. Primaquine could be used for causal prophylaxis during and after exposure or for presumptive antirelapse therapy (PART) in case of high exposure to P. vivax. A radical cure is used to avoid relapse for patients with a confirmed bloodstream infection with P. vivax or P. ovale. In France, primaquine is not approved for prevention and treatment and its use requires a specific temporary authorization.     

Cent quinze cas de paludisme d’importation à Plasmodium falciparum admis en service d’urgence au CHU de Bordeaux

Objectives

The authors had for objective to evaluate the management of a Plasmodium falciparum malaria in a Bordeaux teaching hospital EU.

Methods

One hundred and fifteen patients with falciparum malaria admitted between January 2004 and October 2006 were retrospectively studied and those with ambulatory treatment were questioned by phone.

Results

Fifty per cent of patients had consulted a community physician prior to admission, and a parasitic test was made for 50 % of these. In seven (27 %) cases the test was wrong. Twenty-seven (87 %) of ambulatory patients were contacted by phone. Eleven (41 %) of these said they were not aware of the potential disease severity. Patients initially treated in ambulatory care and later hospitalized because of their evolution have either insisted to go back home or have been sent home because there was not enough room in the hospital. Hospitalization for at least 24 hours had been indicated for 83 patients (72 %). Twelve patients (10 %) have presented with symptoms of severe malaria. Atovaquone–proguanil was the main therapeutic regimen for inpatients and outpatients (n = 93, 81 %). Twelve (10 %) patients did not undergo follow-up parasitological assessment, 10 ambulatory patients (32 %) and two hospitalized patients (2 %).

Conclusion

An efficient hospital-community network and recent protocols are the best tools to rapidly refer patients to an adapted structure with available trained staff and referent specialist.     

Efficacy of chloroquine, sulfadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria among children under five in Bongor and Koumra, Chad

We report two 28-day in-vivo antimalarial efficacy studies carried out in the urban centres of Bongor and Koumra, southern Chad. We assess chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to treat Plasmodium falciparum uncomplicated malaria. Methods and outcome classification complied with latest WHO guidelines. Out of the 301 and 318 children aged 6-59 months included in Bongor and Koumra, respectively, 246 (81.7%) and 257 (80.8%) were eligible for analysis. In Bongor and Koumra, the 28-day PCR-adjusted failure rates for CQ were 23.7% (95% CI 14.7-34.8%) and 32.9% (95% CI 22.1-45.1%), respectively, and those for SP were 16.3% (95% CI 9.4-25.5%) and 4.3% (95% CI 1.2-10.5%). AQ failure rates were 6.4% (95% CI 2.1-14.3%) and 2.2% (95% CI 0.3-7.6%). The current use of CQ in Bongor and Koumra is questionable, and a more efficacious treatment is needed. Considering the reduced efficacy of SP in Bongor, AQ seems to be the best option for the time being. Following WHO recommendations that prioritize the use of artemisinin-based combinations, artesunate plus amodiaquine could be a potential first-line treatment. Nevertheless, the efficacy of this combination should be evaluated and the change carefully prepared, implemented and monitored.     

Temporal variations in immune responses to conserved regions of Plasmodium falciparum merozoite surface proteins related to the severity of a prior malaria episode in Gabonese children

We measured cellular and humoral responses to conserved regions of Plasmodium falciparum merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) at different times during and after acute infection in matched groups of Gabonese children who presented with either mild or severe malaria. We used an MSP-1(19) recombinant protein and peptides corresponding to conserved epitopes in MSP-1 and MSP-2 N- and C-terminal regions. The prevalences of peptide-induced cell-mediated responses were maximal in both groups when they were healthy, but were consistently higher in the mild malaria group, whereas peptide-specific antibody responses were consistently highest in the severe malaria group. Recombinant MSP-1(19) protein-specific antibody levels in the 2 groups were similar both prior to and 1 month post-treatment but declined later when the children were healthy and parasite-free, to a significantly lower level in those admitted with severe malaria, reflecting the profile of the predominant MSP-1(19)-specific immunoglobulin G1 isotype. This finding implies a defect in the ability of children with a history of severe malaria to maintain an antibody response putatively associated with immunity to P. falciparum malaria.     

A prospective study of Plasmodium falciparum multiplicity of infection and morbidity in Tanzanian children

Several studies suggest that in individuals with substantial previous exposure to malaria, co-infection with multiple clones of Plasmodium falciparum can protect against subsequent clinical malaria attacks. Other studies, mainly of individuals with little previous exposure, found the converse relationship. To test whether acquisition of such cross-protection tracks the acquisition of clinical immunity in general, 610 Tanzanian children aged 0-6 years were enrolled in a nine-month prospective study of the risk of morbidity in relation to parasitological status and merozoite surface protein 2 genotypes on enrolment. Prevalence of parasitaemia and multiplicity of infection increased with age. In the first year of life, the incidence of clinical malaria was almost three times higher in children with parasites at baseline than in those without. In older children, baseline P. falciparum infections appeared to protect against both parasitaemic and non-parasitaemic fever episodes. In children aged less than three years, baseline multiple infection tended to be associated with higher prospective risk of clinical malaria than single infection while in children aged more than three years the converse was found, but these effects were not statistically significant. These results provide further evidence that relationships between asymptomatic malaria infections and clinical malaria change with cumulative exposure.     

Complications and mortality patterns due to Plasmodium falciparum malaria in hospitalized adults and children,Rourkela, Orissa,India

Of 1857 Plasmodium falciparum malaria patients hospitalized from 1995 to 1998, 608 had severe malaria and 83 died. Acute renal failure, jaundice and respiratory distress were common in adults whereas children frequently had severe anaemia. Cerebral malaria occurred equally in adults and children but recovery from coma was quicker in children. Multiple complications caused high mortality in adults.     

Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02A administered alone or concurrently in rhesus monkeys

In an effort to broaden the immune response induced by the RTS,S/AS02_A,vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1₄₂ and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1₄₂ and AMA1 vaccines formulated with the AS02_A Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1₄₂ or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1₄₂ and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-γ and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1₄₂ and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1₄₂ lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1₄₂ significantly reduced AMA1 IFN-γ and IL-5 responses. MSP1₄₂ suppression of AMA1 IFN-γ responses was not seen in animals receiving RTS,S + AMA1 + MSP1₄₂ suggesting that RTS,S restored IFN-γ responses. Conversely, AMA1 had no effect on MSP1₄₂ antibody and IFN-γ and IL-5 responses. Neither AMA1 alone or combined with MSP1₄₂ affected RTS,S antibody or IFN-γ and IL-5 responses. Immune interference by MSP1₄₂ on AMA1 antibody responses was also evident when AMA1, MSP1₄₂ and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.     

Chloroquine blood concentrations and molecular markers of chloroquine-resistant Plasmodium falciparum in febrile children in northern Ghana

Plasmodium falciparum malaria is a predominant reason for health care utilization among children in sub-Saharan Africa. Despite the spread of resistance, chloroquine (CQ) is the most commonly used antimalarial. Little is known about the pattern of CQ use and resistance to the drug prior to attendance at a health care facility, and its impact on clinical presentation in children attending health care facilities in endemic regions. In a cross-sectional study among 840 febrile children presenting at a primary health care facility in northern Ghana from September to December 2000, CQ blood levels were measured by enzyme-linked immunosorbent assay and parasite isolates were genotyped for the CQ resistance markers pfcrt T76 and pfmdr1 Y86. Plasmodium falciparum was present in 95% by polymerase chain reaction and CQ was detected in 64% of the children. Concentrations of CQ in blood ranged from 31 to 3897 nmol/L (median 198 nmol/L). The pfcrt T76 and pfmdr1 Y86 resistance markers were detected in 84% and 57% of the isolates, respectively, and were selected by CQ. A significant trend for higher frequencies of the resistance markers with increasing CQ concentrations was observed. In this typical primary health care setting in sub-Saharan Africa, CQ use prior to attendance at a health care facility and CQ-resistant P. falciparum are frequent. As CQ selects resistant P. falciparum genotypes, CQ should be omitted as a first-line drug even in primary health care facilities when self-treatment with CQ is common.     

Le doripénème : quelle place pour un nouveau carbapénème ?

Doripenem is a new member of the carbapenem family. Its spectrum is a little wider than meropenem and it is active on some Pseudomonas aeruginosa strains resistant to other carbapenems and on Burkholderiacepacia. Doripenem was evaluated in nosocomial pneumonia including ventilator-acquired pneumonia, complicated intra-abdominal infection, and complicated urinary tract infection. In nosocomial pneumonia, doripenem showed an interesting activity in P. aeruginosa infected patients. This data, along with the global increase in multiresistance, may be an opportunity to optimize our therapeutic options with a new molecule.     

Concurrent dengue and malaria due to Plasmodium falciparum and P. vivax

Concurrent infections of dengue and malaria are rare. We report a case of dengue fever with acute malaria due to Plasmodium falciparum and P. vivax in which the presence of mixed infection with P. vivax was overlooked and confirmed later on during recurrence of the fever that had initially responded to conventional antimalarial treatment and symptomatic treatment for dengue fever. We suggest that in concurrent infections of dengue and malaria, possibility of mixed infection with various Plasmodium species should be excluded to ensure a better treatment outcome.     

Low prevalence of Plasmodium falciparum infection among asymptomatic individuals in a highland area of Kenya

In areas of highly seasonal Plasmodium falciparum transmission, the presence of a large reservoir of persistently infected but asymptomatic individuals in the dry season leads to predictable increases in the incidence of clinical malaria in the rainy season. Highland areas, by contrast, are prone to unpredictable epidemics of malaria. To determine the importance of persistent asymptomatic infection in highland areas, we assessed asymptomatic individuals in the highland area of Kipsamoite, Kenya for the presence of P. falciparum blood-stage infection by microscopy and PCR. Five sample collections were performed during rainy and dry seasons over a 31-month period. The final collection was obtained at the start of a rainy season epidemic. Asymptomatic parasitemia was infrequent, ranging from 1.3 to 8.1% by microscopy and 5.9 to 14.5% by PCR testing. Microscopy had low sensitivity (22.2-54.8%) but excellent specificity (95.4-100%) in comparison to PCR testing. Frequency of asymptomatic parasitemia did not differ by age. Gametocyte prevalence was <1% in all periods, except at the start of the epidemic, when it increased to 5.3%. In this epidemic-prone highland area, inter-epidemic periods are characterized by low frequencies of asymptomatically infected individuals. Increases in gametocyte prevalence may be an early indicator of impending outbreaks.     

Muscle cell injury, haemolysis and dark urine in children with falciparum malaria in Papua New Guinea

During a prospective study of red cell variants and severe malaria in children, a surprising observation was the occurrence of dark urine. Children were grouped according to urine findings: 22 had dark urine that contained a haem protein (Group I), 93 had urine of normal colour that contained a haem protein (Group II) and 236 had normal urine (Group III). To investigate the cause of dark urine, haemolysis and muscle cell injury were assessed. Intravascular haemolysis was greater in Group I than in Groups II and III. However, anaemia was more severe in Group III and is likely to have resulted mainly from extravascular haemolysis. Median plasma myoglobin concentrations were greater in Groups I and II than Group III (P = 0.00060). Plasma myoglobin was greater in children with cerebral malaria, hyperlactataemia and those who died but was not associated with acidosis. Urine myoglobin was greater in Group I than Groups II and III (P = 0.00054). It is likely that both haemoglobin and myoglobin contributed to dark urine. The association between muscle cell injury and coma suggests sequestration of parasitized red cells as a common underlying pathology. In malaria, hyperlactataemia may result directly from breakdown of muscle protein as well as tissue hypoxia.     

The incidence of clinical malaria detected by active case detection in children in Ifakara, southern Tanzania

Between July 2000 and June 2001, we used weekly active case detection (ACD) of clinical malaria episodes in 618 children aged < 5 years to describe the epidemiology of malaria in Ifakara, southern Tanzania. Plasmodium falciparum-positive blood slides prepared from children with axillary temperature 37.5 degrees C were used to define clinical malaria and a rolling cross-sectional survey documented the prevalences of parasitaemia and anaemia. A random subsample of children was visited daily for 1 month at the end of the study to assess the effect of more frequent visits on estimated incidence rates. Only 50 (8%) children had 1 or more episodes of clinical malaria during the year, an overall incidence of 0.275 episodes/100 child-weeks-at-risk, with no age dependence. The maximum parasite prevalence of 25% was reached in children aged 4 years. The incidence of illness was significantly lower in children visited daily than in those visited weekly, suggesting a marked effect of frequent visits on estimated incidence rates. We conclude that the age pattern of malaria detected through ACD is a more robust epidemiological indicator than absolute incidence rate estimates and that, in contrast to the surrounding area, Ifakara town is subject to only moderate perennial malaria transmission.