Paludism

Epidemiology of plasmodium

Paludism is the parasitic disease most widespread in the world: the estimates of the number of contaminated people vary between 300 and 500 or 660 million and it kills more than one million people per annum, the majority in Africa. It is the first cause of mortality of the children of less than five years in Africa. The expectant mothers in the endemic zones, are also particularly touched by paludism because the Placenta constitutes a target where the parasites ( Plasmodium falciparum ) can accumulate. Paludism is still the world disease most important (priority of 1st rank for WHO) as well by its direct devastations as by its socio-economic consequences: an unproductiveness leading to the Malnutrition and the underdevelopment

It should be noted that the human being is far from being the only host to undergo paludism. For example, many are the birds, in Europe and throughout the world, which are carrying these parasites, in particular of Plasmodium relictum .

Morphology of plasmodium

The plasmodium, discovered by Laveran with Constantine in 1880, is a very small Protozoaire 1 to 2 µ according to the forms; coloring with the May-Grünwald-Giemsa watch which it consists of a pale blue cytoplasm surrounding a clear nutritive vacuole, and containing a red core and brown-gilded or black pigment (Hémozoïne).

Biology of plasmodium

The rather complex evolutionary cycle requires 2 hosts, a final host, the Homme, and an intermediate host and vector, the female Hématophage of a mosquito of the kind Anophèle. From a strictly biological point of view, the true final host of this hématozoaire, is the mosquito (sexuée reproduction parasistant Anophèle). The man would be only one host intermediate in his replicative cycle. Nevertheless, for ethical reasons, will say, one considers that the vector is not the man, but the mosquito. Thin spindle of 12 µ/1 µ, the Sporozoïte infectious is injected with the healthy man at the time of the puncture of a infectious Femelle of anophèle. It reaches the liver in 1/2 hour and penetrates in a Hépatocyte: it is the beginning of a crisis pre-érythrocytaire hepatic which will last 6 days for P. Falciparum, 8 days for P. Vivax, 9 days for P. Ovale and probably 12 days for P. Malariae. The plasmodium Cryptozoïte will undergo in the hépatocyte an intense multiplication Asexué E leading to the blue Corps, enormous ripe Schizonte from 40 to 80 µ. This blue body then buds so as to emit blisters containing the young people Mérozoïtes. These blisters of dead membrane are not phagocytées by the Macrophage S because of an action Biochimique of the parasites on the membrane, which remove the signals of phagocytic destruction of the dead cells. These blisters are released in the hepatic Sinusoïdes to join blood circulation then. It is a true technique of Trojan horse which is used here to pass from the hepatic cells to the Sang. The blisters then release there a flood of young people Mérozoïte S pre-érythrocytaires who will spread themselves there. It is the beginning of the long blood phase: the Mérozoïte S are joined with the érythrocyte S (margination), invade them, develop Trophozoïte S to with it then divide there (Schizonte S), the bursting of the ripe schizontes or " rosaces" finish the schizogonic first cycle érythrocytaire while releasing in blood, with waste of the metabolism Plasmodial (cellular pigments and remains), a new generation of plasmodiums, the Mérozoïte S érythrocytaire S. a regular succession of similar cycles will follow, which will be gradually replaced, the immunizing Défenses organizing itself, by gamogonic cycles érythrocytaires preparing the sexuées forms: the Trophozoïtes, instead of dividing, modify their nucléo-plasmatic ratio and give forms to a core bulky and a densified Cytoplasme, the Gamétocyte S male S and females, which will remain on standby in circulating blood. Swallowed by a female anophèle, these gamétocytes finishes the sexué cycle: become gamètes male and female they are combined giving the ookynète, which after having crossed the wall, stops on the external face of the gastre, becomes oocyst then sporocyst; its bursting releases the infectious sporozoïtes which accumulate, on standby, in salivary glands, thus making the female of anophèles infectious. When this female pricks a healthy man, it will inject the sporozoïtes with its saliva and the evolutionary cycle will be buckled. For P. Falciparum it is there all the biological evolution with P. Vivax, P. Malariae and P. Ovale some pre-érythrocytaires mérozoïtes, do not gain blood, but attack new hépatocytes: it is the beginning of the secondary cycles exo-érythrocytaires which will maintain in the liver the parasitosis during 3 to 5 years or more for P. Vivax, 2 or 3 for P. Ovale and during the whole life for P. Malariae.

Cycle plasmodium

At the time of a meal of Blood, the mosquito injects the parasite with its Hôte. This one is then appeared as a Sporozoïte. It circulates in the Sang to penetrate in the Foie a half hour afterwards. It multiplies there then by cellular divisions during 10 to 15 days. This phase also will make it possible the parasite to survive a long time in the organization, whereas it disappears from blood. It is what explains the relapses for two in the long term Plasmodium: Plasmodium vivax and oval Plasmodium . This phase of the parasite is called dormant Phase: Plasmodium is not retorted but sleeps, from where the name which is given to him at this time: Hypnozoïte S.

When they are released from the liver, the sporozoïtes changed form and become Mérozoïte S. Those circulate in blood and will infect the red Globules. They nourish Hémoglobine and multiply. Then they are diffused while making burst the Hématie S (the scientific name is called Hémolyse). These are the brutal and synchronous burstings which are at the origin of the access of Fièvre. The time which was passed between the penetration of a parasite in a red Globule and the bursting of this one reached at the human being 48 hours for Plasmodium vivax , oval P. and P. falciparum (third Fièvres) and 72 hours for P. malariae (Quartan fever). The destruction of the Hématie S causes a Anémie and, in the case of the cerebral Paludisme, the Mort intervenes following an obstruction of the blood-vessels of the Cerveau by the infected red globules. This destruction of red globules is accompanied by the release of Hémozoïne, which will disturb the operation of the very strong Hypothalamus and will cause Fièvre S which can go until the Hyperpyrexie.

The released mérozoïtes will parasitize other red globules and the asexual cycle continuous.

After some asexual cycles parasites of special form appear, the Gamétocyte S which remain in peripheral blood, they are sexuées forms produced by the Plasmodium .

The parasites at the time of this phase do not have any chance of survival in the human being. They remain alive a score of days then disappear. They will be able to continue their evolution only in the mosquito. At this time if a Anophèle spade a sick person, it absorbs gamétocytes contained in blood, and a new cycle, sexué that one, begins in the arthropod vector.

The imagery in vivo showed in 2005-2006 in rodents that the mérozoïtes were able to manufacture dead cells a Trojan horse enabling them to leave the liver for blood circulation while escaping the immune system.
La cell of liver infected contains approximately 10.000 mérozoïtes. She dies under the effect of the infection by changing of structures known as Mérosome S ” which full with parasites gains the vessels sinusoids of the liver to emerge in the blood system where the mérozoïtes disperse. The mérozoïtes at the same time seem to guide this vehicle and to hide there. They seem to preserve it by masking the biochemical signals which alert normally the Macrophage S. There is perhaps there a new track for active drugs before the stage of the invasion of the red globules.

Private clinic of paludism

The clinical demonstrations of paludism appear only during the asexual multiplication of plasmodiums inside red blood corpuscles making of paludism, with the clean direction, a parasitic erythrocytopathy. The latter ends in:

of the feverish accesses violent one and rates/rhythms;
a massive red blood corpuscle destruction (direct and indirect) which involves a haemolytic Anémie and reaction of the S.R.H. (Splénomégalie progressive);
a pigmentary Biligénie, from where Subictère (and Hepatomegaly of recovery);
a deterioration of the general state which can lead to the Cachexy.

The study of the cycles (see higher) makes it possible to include/understand the course of a paludism untreated.

The 6 to 10 accesses constituting the reached primoinvasion will be followed attacks semblabes of recrudescence as long as the latent state the parasitemy responsible for the first attack will last, that is to say 2 months to 2 years according to plasmodium. For P. Falciparum the things will be arrèteront there.

For plasmodiums recurring (P. Vivax, P. Ovale and P. Malariae) of news reached recurrence due to blood réinfestations at the beginning of the hepatic cycles exoérythrocytaires secondary can prolong the infection within the times already indicated. The typically rythmées attacks of the traditional form, hardly any more appear today, even in the zone of endémie because of employment generalized of chimiotherapic drugs and chimioprophylactic. They still meet in the " paludisms with the seringue" which one respects the normal evolution with a therapeutic aim (Malariathérapie) and in recurring paludisms.

Various types of paludism

The serious complications relate to in general only Plasmodium falciparum , which explains the absence of chimioprophylaxie for the voyages in regions where only P. vivax prevails (the Maghreb for example).

Simple paludous accesses

The crisis of paludism , also called paludous access , is characterized by feverish accesses, with a fever with more 40°C, shivers, follow-ups of a fall of temperature accompanied by abundant sweats and of a feeling of cold.

Classically, one distinguishes the third fever (i.e. occurring every 2 days) due to Plasmodium vivax and oval Plasmodium (benign third fever) and Plasmodium falciparum (malignant third fever) from the quartan fever (i.e. occurring every 3 days) due to Plasmodium malariae (the term “malaria” indicated the quartan fever specifically).

These paludous accesses can be repeated during months even years with oval Pl. , Pl. vivax and Pl. malariae , but not with Pl. falciparum , if they are correctly treated and in the absence of reinfestation (case of the paludism of importation, in general)

Currently, the diagnosis is rather suspecté, at the time of a feverish episode (in general, 40°C or more) alternating with big chills, abundant sweats and a feeling of cold, to the return of an infested zone .

Evolutionary visceral paludism

Formerly called paludous cachexy , associating moderated intermittent fever, weakens and Cytopénie, Splénomégalie moderate in children from 2 to 5 years. In evolutionary visceral paludism, the organization is obviously overflowed, and it should be defended at all costs while attacking the blood and tissue forms successively:

Chloroquine (Nivaquine*) 600 Mg (2 compressed to 0,30 G) per day the first 2 days, then 300 Mg (1 compressed to 0,30 G) per day 3 following days then,

Primaquine* 15 Mg (3 compressed to 0,5 Mg) per day during 15 days, 6th at the 20th day is included.

It is necessary to supervise the signs of intolerance to 8-ammino-quinolines (giddinesses, nauseas, diarrhea, Cyanose, Hémoglobinurie, Agranulocytose) although they are rare with this posology.

The hemoglobinuric bilieuse fever

Complication currently extremely rare occurring at individuals in the past reached of the malaria with alive plasmodium falciparum in the countries of strong endémie (where most of the population is touched) and dependant on the catch of Quinine or other molecules (Halofantrine). It is secondary with a bursting of the red globules inside the vessels (intravascular Hémolyse). It is characterized by

a Fièvre raised,
a state of shock with Prostration,
a Ictère,
of the dark urines more and more containing hyaline Cylindres,
a Anémie,
a Hémoglobinurie (presence of hemoglobin in the urines, giving them an Oporto color),

and especially

a Impaired renal function mortal due to a destruction of the renal Tubules (necroses tubular acute).

It is a medical emergency as well as the pernicious access. The treatment will have 3 goals:

to control the oligo-anurie
déparasiter the patient
to treat haemolytic anemia

Against the oligo-anurie, the Dialyze péritonéale will make it possible to cross the critical phase while waiting for the re-establishment of the diuresis. Against the parasitemy, an absolute veto against the Quinine, completely contra-indicated here by the hémolyse like against the Sulphamide S (renal tubulopathy). One will be satisfied with:

Chloroquine (Nivaquine *) at a rate of a single injection of 300 Mg per intramuscular way.

Against haemolytic anemia, one will practice with the choice:

of the transfusions, spared and resolutely of the same blood group, or, better, when it can, of the Exsanguino-transfusion S.

Nephritis quartane

The plasmodium malariae is likely to involve an infection with repetition (or chronicle) attacking the clusters, at the origin of a nephrotic syndrome by the dissolution of immunizing complexes (associations antibody-antigen). All the subjects presenting an infection repeated by plasmodium malariae do not present a renal attack. The examination under the electron microscope of the renal taking away makes it possible to identify the lesion. This examination highlights deposits additional (elements intervening in the immune system) and of immunoglobulins (variety of proteins playing the part of antibody). The laboratory detects in the child of the antigens of plasmodium malariae. The forecast is better when they are deposits immunofluorescents to prevalence of IgG3 and coarse granulation with protéinurie selective (the kidneys let pass only one certain variety of proteins and not all). The subjects presenting of the granulous fine deposits to prevalence of IgG2 and a nonselective protéinurie (the kidneys let pass all proteins) have a less good forecast. Treatment: nephritis quartane always does not answer the treatments antipaludic nor corticoids like with the cytotoxic drugs.

Serious paludous accesses to Plasmodium falciparum which is most frightening of 4 paludisms

Paludous pernicious access

or neuropaludism or cerebral paludism

It is a cerebral malaria associating an important rise in the temperature (40°C) and one coma of bad forecast in spite of the treatment and for which mortality amounts sometimes to 20% in the adults and 15% in the children. The appearance of a severe malaria is either progressive or brutal. It begins after instantaneous and momentary convulsions from one or more muscles, followed relaxations.

They are located or generalized with the whole of the body. This variety of the malaria is accompanied by a Nystagmus (jumping of the eyes in the horizontal plane in a ceaseless way), sometimes of a stiffness of the neck and a disturbance of the reflexes. In approximately 15% of the cases, there exist hemorrhages of the retina (layer of cells papers the retina). The severe malaria is accompanied by an anemia and a ictère (jaundice). The convulsions occur primarily in the children and only in 50% of the cases in the adult. The other signs of this type of the malaria are the Hypoglycémie (drops sugar rate in blood) which is bad forecast. This symptom touches the children particularly and the expectant mothers, it is with a faulty operation of the liver and an exaggerated sugar consumption by the parasite. The expectant mothers are particularly predisposed with hypoglycemia. The Lactic acid , which involves an increase in the acidity of blood, is also of bad forecast.

The pulmonary edema (presence of liquid in the lungs) is not well explained but can be at the origin of a death rate exceeding 80%. The attack of the kidneys is rarer in the child and is also accompanied by a strong mortality. Its mechanism is not cleared up either. The anemia noted during the severe malaria is the result of the destruction and elimination accelerated of the red globules by spleen, associated with a deficit of production of these globules by osseous marrow (medullary aplasia). It generally requires a transfusion. This one poses problems in the child and is at the origin of the presence of hemoglobin in blood, of urine of black coloring and the insufficiency of operation of the kidneys. Another complication likely to occur during this variety of the malaria is the hemoglobinuric bilieuse fever. One also attends a Hématémèse due undoubtedly to an attack of the stomach by ulceration due to the stress.

The malaria of the expectant mother

The infection of the Placenta by the plasmodium falciparum results in a weak weight of birth, particularly when it is about a first Accouchement (Primipare).

When the quantity of parasites in blood is relatively not very important (it is the case in the zones of stable transmission), the women do not present a signs whereas the parasites which invade the red globules of circulation, and more precisely of the small circulation of the placenta, are present. In the zones where the transmission is unstable (one speaks about hypo or of méso-endémie), the expectant mothers present severe infections associated with quantities high with parasites in blood with a Anémie, a Hypoglycémie and oedemas of the lungs. The Grossesse is then enamelled problems with type of premature contractions, miscarriage and mortality at the time of the childbirth. The congenital malaria touches approximately 5% of the new-born babies of infected mothers and is in direct relationship with the quantity of parasites in the placenta.

The transfusional malaria

It is a malaria transmitted via a blood Transfusion or after exchange of needles between doped individuals. Plasmodium malariae and plasmodium falciparum are generally blamed. In this case, the incubation period is short because there does not exist pre-érythrocytaire cycle (being held before the invasion of the red globules). The transfusional malaria results in same the signs as those which one observes by plasmodium. Nevertheless, the plasmodium falciparum is generally severe at the drug addicts. Treatment, which uses the primaquine when it is about a infection with oval plasmodium or vivax, is then useless, because of difference of the cycle of transmission of the transfusional malaria.

The malaria of the child due to falciparum

Origin from approximately 1 to 3 million death each year. This variety of the malaria touches primarily the Africans and is accompanied by:

Central nervous system disorders with Convulsion S which can go until the Coma
Hypoglycemia
Increase in the rate of acidity of blood (Metabolic acidosis)
severe Anemia

Contrary to the other forms of the malaria, the malaria of the newborn is seldom not accompanied or by a renal attack with type of insufficiency of filtration of the kidneys ( Impaired renal function) nor of a liquid collection in the lungs (acute edema pulmonary). In this variety of the malaria, the treatment is generally effective and fast.

The tropical splénomégalie

Currently named splénomégalie paludous hyper-immune , this Splénomégalie meets at some individuals who live in a zone where the malaria is endemic. These people present an abnormal answer immunological to the infections due to the malaria, which is translated, apart from the splénomégalie, by a Hépatomégalie, the rise in a certain type of immunoglobulins in blood (IgM, anti-paludous antibodies) and of the number of Lymphocyte S inside the hepatic sinusoids.

The Biopsy of the Liver and the examination with the optical Microscope make it possible to carry the diagnosis.

Symptoms:

abdominal Tugging.
Presence of an abdominal mass.
violent abdominal Pains (perish-splenic: ignition of fabrics surrounding spleen).
Anemia.
the laboratory does not show the presence of parasites in blood.

Infections with repetition:

Complications: raised death rate, proliferation of the lymphocytes with appearance of a malignant lymphoprolifératif syndrome likely to develop at the individuals having a antipaludic resistance to the treatment

General symptoms at the human being

After a fifteen or so days, following a stay in a zone at the risks, one observes:

Tiredness generalized.
Tremor S by intermitence.
Loss of Appetite.
Giddiness S.
Hyperthermia (fever), generally irregular at the beginning.
Shiver S.
Cephalgia S (headaches).
Digestive disorders (stomach upset), nausea S, Vomiting S, abdominal pains.
Diarrhea.
Myalgia S (muscular pains).
Arthralgie S (joint pains).
Ictère (jaundice).

Diagnosis

The diagnosis of certainty rests on the description of the parasite in blood, by blood Frottis or thick Goutte.

Five species of plasmodium pathogenic for the human being, but are differentiated by their geographical distribution and their pathological effect:

Plasmodium falciparum , person in charge of the lethal and guilty form of more than 90% of the deaths,
Plasmodium vivax ,
Plasmodium malariae ,
oval Plasmodium (Gabon, Madagascar) ,

Plasmodium knowlesi of recent discovery, related with P. malariae .

The disease results primarily in an intermittent fever. The treatment and the individual Prophylaxie call upon derived from the Quinine.

Means of fighting the mosquito

One can fight the vector of paludism (the female anophèle) by several means of prevention which can prove to be effective if they are well implemented.

One can give for proof the example of the island of the Réunion where paludism prevailed as in the other islands of the area (Madagascar and Mauritius) in particular. The Meeting being a French territory overseas, the problem of the too high cost did not exist and one could éradiquer the malaria of this island without difficulty.

Two modes of prevention are applied in the countries concerned. They aim on the one hand protecting the populations against the punctures from mosquitos and, on the other hand, at eliminating the latter by the installation from various means. The principal goal of this Prophylaxie is to limit the population of Moustique S vectors of the disease and thus to try éradiquer this plague.

In the years 1960, the principal method used for éradiquer the female anophèles was the massive use of insecticides (more used being DDT (Dichloro-Diphényl-Trichloréthane)). This method bore its fruits in many areas where paludism was completely éradiqué. Unfortunately, the intensive use of the DDT supported the appearance of species of resistant mosquitos. This resistance was named KDR ( Knock Down Resistance : resistance to the effect of shock). Moreover, the DDT can generate intoxications and diseases in the population.

To replace the DDT, which proved to be dangerous and less and less effective, of the alternative means were deployed in order to fight the vector of paludism:

of measurements of cleansing: draining of the marshes, drainage of stagnant water where the larvae of the Anophèle S develop;
anti-larval fight by oil spreading and use of widespread soluble insecticides at water surface stagnant, to try to limit the births of anophèles. One can also sow water with predatory anophèles (fish, molluscs);
use of insecticides with small scales: insecticide pulverization intradomicilaires (Pyrethrinoid S) in the dwellings (rooms to lay down, impregnate the mosquito nets of pyrethrinoid…) ;
recourse to fish (Tilapia S, Guppy S, Gambusie S, Aphanius) which eat the larvae of mosquito;
dispersion of sterile males anophèles in nature;
genetic interventions on the species vectrices.

Unfortunately, these measurements are effective only on one limited territory. It is very difficult to apply them on a continent scale such as Africa.

To a lesser extent, it is possible to avoid the punctures of anophèles by mechanical, physical and chemical measurements:

installation of impregnated insecticide mosquito nets to sleep with the shelter of the possible punctures;
installation of air conditioning in the dwellings cause a drop in the temperature;
wearing of full and long clothing after laying down it sun;
to avoid the walks after laying down it sun;
application of repulsive cream on the skin or clothing to laying down sun;

The last means applied is targeted much more. Indeed it applies only to the expectant mothers, and the purpose of it is to make it possible to the infants to be born in good health and not with a too weak weight or reached many diseases like placental paludism, serious anemia and the malformation of the baby.

In order to prevent and to prevent large complications, a total assumption of responsibility which comprises a prevention of the paludous infection and the health protection was installation. The purpose of these actions are to limit the infections and their consequences being able to be very serious for the child and the mother. It is in particular about the use of antipaludéens, either on a purely prophylactic basis, or like intermittent treatment, and of the possible recourse to the impregnated insecticide mosquito nets.

It was proven that in the zones of endémies, an effective prevention of paludism during the pregnancy makes it possible to reduce the incidence of anomalies like a weak weight to the birth or a maternal anemia engraves (reduction in the concentration in hemoglobin of blood (in lower part of 0,13 g/ml at the man and 0,12 g/ml at the woman)).

The application of these some rules would be enough cause a drop in considerably the number of people touched by this disease and thus the number of victims. Unfortunately these countries are too poor and do not have enough means to apply them. The majority of the inhabitants do not even have the means of getting mosquito nets whereas those would reduce much risks of infections.

Means of fighting the parasite

One can fight the parasite by applying various molecules:

in Treatment S Curative S;
in Disease prevention.

Curative treatments

Old treatments

One can fight the parasite by applying various molecules either in curative treatments or in disease prevention. These various treatments are more or less effective according to the areas and the rates of resistance contracted because, just like DDT (insecticidal more used in the years 1960), the effective drugs 30 years ago, are not it today. However, these obsolete formulations are still massively used in the touched countries.

Indeed, these countries are mainly poor and thus do not have the means of migrating their protocol towards a more expensive treatment like the ACT ( Artemisinin-based combination therapy : combinations containing Artémisinine). For a long time, the treatments called upon chloroquine, quinine and the sulfadoxine-pyriméthamine (or Fansidar) and to a lesser extent the méfloquine, the amodiaquine and the doxycycline. These molecules were very effective weapons to fight against the parasites of paludism but their regulation without control supported the emergence of resistant stocks . According to WHO, a treatment is effective if the rate of failure is lower than 5%; if it exceeds 25%, protocol should be changed.

The Chloroquine was managed a long time in priority to look after the patients. It was a drug which had many advantages, in particular its low costs and the absence of side effects. Today, unfortunately, the care containing chloroquine fails more than 25% in the majority of the African countries touched by paludism. However, one continues, despite everything, to employ them.

Where chloroquine does not have any more an effect, one uses a drug called “drug of second intention”: the Sulfadoxine-pyriméthamine (or Fansidar). This molecule circumvents resistance to chloroquine. Five years only were enough so that resistant stocks appear. One then adapts the treatment while resorting to a “drug of 3rd intention”: the Quinine, managed per bone in the benign cases, by perfusion in the acute cases. But one realizes now that this treatment is him also confronted with new resistances.

This resistance is due to the change of a gene of plasmodium, PFCRT . This change would involve however a less good adaptation of the parasite to its medium. The Malawi is the first African country to have given up chloroquine as of 1993, leading to a reappearance of the sensitive stocks which become again then highly majority.

ACT

Vis-a-vis paludism, there exists only one truly effective treatment: the ACT (Artemisinin-based combination therapy: combinations containing artémisinine) such as the Coartem. A treatment recommended by the WHO but which remains still expensive. No resistance for the moment is indexed and its effectiveness was already proven and it is without side effect. The principal disadvantage remains its price, inaccessible for many countries in the process of development.

The Artémisinine, resulting from Artemisia annua a Chinese plant, largely proved its effectiveness in Asia. Studies undertaken in laboratory and in many impaludés countries show at the same time its effectiveness and its facility of administration. It more quickly eliminates the parasites present in blood.

However, if the regulation of Artémisinine, in the form of infusions resulting from Artemisia annua can prove very effective, its use is prone to important measures of precaution, in particular recommended by WHO: it is necessary at all costs to avoid the irreversible selection of resistant stocks resulting from an uncontrolled monothérapie and/or proportionings. Uncontrolled proportionings are inherent in any preparation resulting from plants, since the weather conditions, qualities of the grounds, or the protocols of harvest, often artisanal, are unforeseeable and thus naturally unverifiable. It is consequently very irresponsible to promote for example on broad scale the culture of the plant and the monothérapie only based on the administration of artisanal Tisane of Artemisia annua which in drift.

To increase its effect, but also to delay the appearance of resistances, the Artémisinine is thus managed in partnership with another molecule, SP, amodiaquine or méfloquine: they are the ACT (of English, artemisinin-based combination therapy ), therapeutic combinations associating the Artémisinine with the other antipaludiques ones. The weak parasitemy resistant to the artémisinine is eliminated by the more durable second antipaludéen of action.

In 2002, WHO published a clear recommendation on the need for using the ACT in the countries touched by resistances to the traditional antipaludéens. WHO, on the opinion of international experts, recommends the introduction of polythérapies to replace the monothérapies in the treatment of paludism and recommends in particular the recourse to medicamentous associations containing of derived from artémisinine.

Produced in small quantities, the ACT are more expensive than chloroquine. A treatment of first line chloroquine or SP currently costs between 0,2 and 0,5 dollar whereas a treatment ACT oscillates between 1,2 and 2,4 dollars, is five to six times more than traditional but useless treatments. For many patients, this difference is the price of the life. A price that, unfortunately, well few people in Africa can pay. Only a manufacture with large scales or a very important financial aid of the rich countries will be able significantly to make lower the production costs.

Disease prevention

In order to prevent all contamination at the tourists going in countries where paludism prevails, the researchers set up a prophylactic technique. This technique consists in using a therapeutic arsenal (limiting itself to chloroquine, the proguanil, association pyriméthamine-dapsone, the méfloquine and the doxycycline (preventive drugs)) in order to fight against the mosquitos, parasites and to prevent all unfortunate infections.

It is very dangerous to leave in intense zone of transmission paludism without regular catch a preventive medication, in particular for the children and the expectant mothers who have an increased risk of serious access of paludism.

But because of the increase in the parasitic pharmacorésistance (resistance of the parasites to the products constituting the therapeutic arsenal) and in the side effects specific to the various products, it is increasingly difficult to establish chimioprophylactic directives (search for drug in a rational way). The tourist must, before venturing in countries touched by this plague, to consult his doctor who will indicate the possible counter-indications of the antipaludéens to him. And so that there is no disparity, it would be desirable to see appearing a harmonization of the national and international chimioprophylactic directives.

The drugs antipaludéens do not guarantee an absolute protection against the infection and it is also important to be protected from the punctures of mosquitos (mosquito nets, anti-mosquito products) because even if an adapted treatment were correctly followed, it is possible to make a crisis of paludism, sometimes of late appearance.

According to a French report/ratio of the National Reference Center for the epidemiology of the paludism of importation and indigenous , founded on a study near the 8.000 French having contracted the disease in the year 2000, about half had had recourse to no Prophylaxie.

In 2002, only 10% of the French travellers, in displacement in a zone at the risk, followed a correct therapeutic diagram. In 1990, this percentage was of a third, that explains, partly, the strong recrudescence of the cases of paludism in France, case atypical in Europe, where the contamination is stable or in regression.

Prophylactic diagrams antipaludéens

At March 9th, 2006, the prevention of the paludic risk is organized in 3 levels, classified according to the level of chimio-resistance. Each country at the risk being thus classified in a group. For the hour to leave on a journey, it is advisable to ask for the opinion of its doctor.

Country of group 0: zones without paludism

No the chimioprophylaxie.

Africa: Lesotho, Libya, Morocco, Island of the Meeting, Island Grey waxbill, Seychelles, Tunisia;
America: all cities and Antigua-and-Barbuda, Dutch West Indies, the Bahamas, Barbados, Bermuda, Canada, Chile, Cuba, Dominique, the United States of America, Grenade, Cayman Islands, Falkland Islands, Virgin Islands, Jamaica, Martinique, Puerto Rico, St Lucia, Trinity-and-Tobago, Uruguay;
Asia: all cities and Brunei, Georgia, Guam, HongKong, Islands Christmas, Islands Cook, Japan, Kazakhstan, Kyrgyzstan, Macao, Maldives, Mongolia, Singapore, Taiwan;
Europe: all countries (including the Azores, the Canaries, Cyprus, Federation of Russia, Baltic States, Ukraine, Belarus and Turkey of Europe);
Near and the Middle East: all cities and Bahrain, Israel, Jordan, Kuwait, Lebanon, Qatar;
Oceania: all cities and Australia, Fiji, Hawaiian Islands, the Northern Marianna Islands, Marshall Islands, Micronesia, New Caledonia, New Zealand, Easter Island, French Polynesia, Samoa, Tonga, Tuvalu.

Particular case of the zones of weak transmission

Taking into account the weakness of the transmission in these countries, it is acceptable not to take a chimioprophylaxie whatever the duration of the stay.

It is however essential to be in measurement, in the months which follow the return, to consult in urgency in the event of fever.

Africa: Algeria, Cape Verde, Egypt, Mauritius;
Asia: Arménie, Azerbaïdjan, North Korea, South Korea, Ouzbékistan, Turkménistan;
Near and the Middle East: United Arab Emirates, Oman, Syria, Turkey.

For all the other countries, it is necessary to take a chimioprophylaxie adapted to the visited zone.

Country of group 1: zones without chloroquinorésistance

Chloroquine 100: a tablet each day (it is possible also to take 300mg twice per week) for a person weighing at least 50 kilograms.

Country of group 2: zones of chloroquinorésistance

Chloroquine 100 Mg, a tablet each day and proguanil 100 Mg, two compressed each day, in only one catch during a meal or association chloroquine-proguanil, a tablet per day, for a person weighing at least 50 kilograms (for a person of less than 50 kg, to refer in the chapter on the child traveller). Association atovaquone-proguanil can be advised in alternative to association chloroquine-proguanil. A tablet (atovaquone 250 Mg + proguanil 100 Mg) per day, at the people weighing at least 40 kg. The treatment can be begun the day before or the day departure. The duration of continuous administration of the atovaquone-proguanil in this indication will have to be limited to 3 months, fault of to date having a sufficient retreat in prolonged treatment.

Country of group 3: zones of high prevalence of chloroquinorésistance or multirésistance

Méfloquine 250, a tablet once per week, for a person weighing at least 50 kilograms. For the prolonged stays (lasted higher than 3 months), the chimioprophylaxie must be maintained as a long time as possible and it is recommended to the travellers to quickly contact a doctor on the spot to evaluate the relevance and the benefit ratio/risk of the chimioprophylaxie. Association atovaquone-proguanil can be advised in alternative to the méfloquine. A tablet (atovaquone 250 Mg + proguanil 100mg) per day. The treatment can be begun the day before or the day departure. The duration of continuous administration of the atovaquone-proguanil in this indication will have to be limited to 3 months, fault of to date having a sufficient retreat in prolonged treatment.

Future

Research relating to the Artemisia led to the synthesis of a cheap molecule to which no resistance would be known: OZ 277. A large scales treatment becomes possible.

In November 2005, the Institut Pasteur announced the beginning of the test on the human being of a prototype of vaccine. To conceive it, the researchers studied the mechanisms of the naturally immunized people.

A few days later, professor Alonso of the Université of Barcelona published in his turn of the encouraging results on another type of vaccine. Conceived within the framework of the Malaria Initiative it Vaccinates would prove to be effective in 30% of the cases and would avoid half of the serious crises.

In March 2006, of the researchers of the Center of studies and Research of the Doctors of Africa in collaboration with the University hospital and the Chemistry laboratory of the Coordination (CNRS) of Toulouse showed the effectiveness of various plants of which the Quassia. At the same date, researchers of the Université of Lille I announced to have developed a new molecule, the ferroquinine, by associating the Chloroquinine with Fer which attracts the parasite, this new molecule would be up to 30 times more effective than the chloroquinine.

In September 2006, a team associating the University Paul Sabatier of Toulouse, CNRS, IRD, and the national Natural history museum of Natural history, announces to have isolated one from the active ingredients antipaludic of the herb tea of Quassia used by local populations of Guyana against paludism. (off Ethnopharmacology).

In December 2006, the Academy of Science of the United States received a communication on a new type of Vaccin. It does not help the person infected by a Moustique to fight against the disease, but is transmitted to the Insecte. It acts then against the parasite. The American researchers think empécher thus the contamination at the time of the following punctures. In the long term, that could even slow down to block the propagation of the epidemic.

Defenses for the host: immunity

After several years of repeated infections, the host of plasmodium can acquire an immunity, called prémunition. One notes a great variability of the answers to the paludous infection between individuals living in the same zones of endémie. In areas where the transmission is strong, a great proportion of the children are often carrying parasites of P. falciparum without declaring any symptom. One speaks about tolerance to the infection in which immunity anti-disease plays an important role. With the successive age and contacts Man/parasite settles little by little a prémunition, which calls upon mechanisms of resistance to the infection among which suppressor immunity plays an important role. It is often said that this immunity sterilizing because it is not shown forever in a formal way of total disappearance of the parasites of P. falciparum in the absence of treatment. It is also said that this immunity is unstable because the prémunition disappears in the absence of frequent contacts between the Man and the parasite. In addition, the immunity directed against P. falciparum is strongly specific stocks. These three characteristics of the immunizing response in paludism are at the origin of the difficulties to work out a vaccine.

Defenses for the host: Genetic factors

Genetic factors can protect from paludism. The major part of those which were described are associated with the red globules, of which here some examples:

the Drépanocytose: a modification in the chain ß of the Hémoglobine involves a deformation of the red globules, which produces hétérozygotes which protect better from paludism. The red blood corpuscles are deformed and hemoglobin crystallizes, which prevents the parasite from returning in the red globule (or Hématie). Although this genetic disease is mortal for the subjects homozygotes, the prevalence of the drépanocytose is high in the subjected African populations has a strong pressure of paludism because of the resistance which it gets against the serious accesses of the disease.
the Thalassaemia: it is about a modification of the rates of synthesis of the chains of globines.
the subjects whose érythrocyte S are deprived of certain Antigène S of blood groups, prone FY (- 1, - 2, - 3, - 6), cannot be contaminated by P. vivax nor by P. knowlesi . It is an example of selective advantage of the West African population, where this blood group is very frequent.

Other genetic factors exist of which certain are implied in the control of the immunizing response

Precautions to be taken

The catch of drugs antipaludéens, even by respecting a correct therapeutic diagram, is not enough to protect to 100% against the risk from paludism. It is also necessary to be protected from the mosquitos, to prevent them from returning in contact with their victims, in order to avoid the insect bite.

To avoid displacements in zone at the risk without protection, always to sleep with a mosquito net, even with open air;

To wear long and full, tight clothing with the wrists and the ankles, with closed shoes, impregnated the repulsive one;

To apply the repulsive cutaneous ones to all the body (containing DDT, and thus to avoid for very the young children, the expectant mothers or nursing);

To use insecticides, inside, but also outside;

To sleep with the air conditioning or under a mosquito net (preferably impregnated of insecticide when the body at night can be in contact with the mosquito net);

To protect all the openings by mosquito nets suitable.

The use of repulsive products or anti-insects (such DEET or DDT) and of mosquito nets reduces the risks of infection, but a Chimioprophylaxie remains essential ( Nivaquine , Savarine , Lariam , Malarone ). It is disadvised drinking alcohol while having taken these drugs.

The not-techniques difficulties

Policy

It was the case for Burundi, in autumn 2000: the use of the ACT was prohibited there, only ineffective drugs because neutralized by resistances of the parasites were used at the beginning of the epidemic. Doctors without borders (MSF) had to negotiate during months to obtain the right to cure its patients.

The arrival of governmental organizations, like MSF, is not always seen of very an good eye on behalf of the leaders, in particular in areas where the political situation is unstable or in authoritarian regimes.

Indeed, MSF registered in its charter the duty to denounce very reached with the Human rights. To preserve of a possible international scandal, certain States do not hesitate to block the good performance of the humane missions , being thus opposed to the principal help of outside.

Economy

According to the League against paludism, a touched family would collect only 40% of her agricultural production, because of lost day's works. WHO even calculated that the African GDP would exceed of 115 billion euros its current level, that is to say 32% additional, if one had eliminated paludism 35 years ago.

In the field of the fight, the UNICEF estimates that the annual average costs of the programs antipaludéens in each country of Africa would be assembled to approximately 345.000 euros, that is to say, for a country of 5 million inhabitants, seven centimes of euros per capita!

The populations located in zones impaludées alive in their vast majority in poverty, the new drugs, definitely more effective but more expensive than the old ones, are very often beyond their means.

It arrives even sometimes that a patient entirely does not follow his treatment and, feeling cured, that it will sell what remains to him at the black-market, thus accelerating the appearance of resistances to the treatments (see chapter on the resistance of the parasite).

According to the figures, the private sector devoted, in 1990 and by victim, 789 dollars to fight the Asthme, 3274 for the AIDS (whose virus relates to the countries in the process of development as much as the developed countries) and only 65 dollars with regard to paludism. In other words, the sum devoted in the search of vaccines and the development of drugs antipaludéens is ridiculous when it is known that nearly 50% of the world population is threatened.

Moreover, the great majority of the countries touched by the malaria have neither the economic means, nor the technological means to develop in their country a real research in the medical field. Countries with financial means very limited (generally collapsing under the weight of the foreign debt), a lack of solid political will, a budget seek quite lower than waitings and a ridiculous international assistance compared with the needs for the populations and the number of touched people, remind that the so disastrous consequences of this disease of the underdevelopment are not entirely due to nature, that the human being is there for much.

However WHO founded in 2001 Funds World to fight against the Malaria, but also against the AIDS and the Tuberculose.

Since 2003, the Foundation Bill & Melinda Gates, also poured several hundreds of million dollars, amongst other things with the Malaria Vaccinates Initiative, to fight against the disease.

Malaria and History

In India, as of antiquity, the Veda give a report on the paludic fevers and the doctors Charaka and Sushruta (probably Ve century before J.C.) make of it a description and associate the puncture of mosquito to him.

In Metropolitan France, the malaria disappeared only relatively recently. It was still present in 1931, in the Marais poitevin, the Golfe of Morbihan and in the Camargue. It was éradiquée of Corsica, where one found it in the Eastern plain, in 1944. The troops states-unien born made it disappear by massively treating the zone with DDT. Unknown of the time of the Roman presence, paludism was introduced at the time of the raids Vandales. The island will know its two epidemics with Plasmodium vivax in 1970 (31 cases) and 1971 (19 case). Since, all the cases observed in France (1025 cases in 1986) are paludisms of importation.

Areas at the risks

After having prevailed in almost the totality of the inhabited world, paludism touches the 90 countries, primarily poorest of Africa, Asia and Latin America. In 1950, paludism was éradiqué of most of Europe and most of the Central America and South. The disease also touches the tourists: on a hundred and thousand of them going in a impaludée zone, three thousand return in their country infected by one of the known shapes of plasmodium.

the Africa is a continent particularly touched by paludism; it relates to 95% of the cases imported in France. The danger is quasi-no one in North Africa, but major in East Africa, sub-Saharan Africa and equatorial Africa.

In Asia, paludism is absent from big cities and rather rare in the coastal plains. The danger is major in the rural areas of the Kampuchea, of the Indonesia, the Laos, the Malaysia, the Filipino , the Thailand, the Vietnam and in China in the Yunnan and with Hainan.

In the the Antilles, paludism prevails with Haiti and close to the Dominican border .

In Central America, there exist some microphone-zones, but the risk is relatively weak.

In South America, the risk is weak in the big cities, but real in the rural areas in Bolivia, in Colombia, Ecuador, with the Peru and the Venezuela, and major in all the zone Amazonia.

It should be noted that the anophèle (vector of the malaria) cannot live with the top of a certain altitude, therefore there is no possible contamination in the mountainous regions of the countries touched by paludism. For example, with Madagascar, paludism prevails along the coasts but not in the capital Tananarive located at approximately 1400 meters of altitude.

The purpose of the most recent cartography of the endemicity of paludism dating from the years 1960, the Malaria Atlas Project, financed by Wellcome Trust (the United Kingdom), is to develop an updated chart. This one should in particular make it possible to better target the campaigns of the fight against paludism and to develop models making it possible to estimate the populations at risk.

Obligatory declaration

In France, this disease is on the list of the Infectious illness to obligatory declaration.

Philately

Paludism was often illustrated on stamps. The first example is a stamp of benevolence of the Mexico emitted in 1939 which shows an human being victim of a giant mosquito. But most spectacular was the simultaneous emission of 1962 in a hundred country celebrating the countryside of WHO entitled eradication of paludism .

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