Malaria basics

Malaria basics

World Health Organization18 March, 20121 The main pointsThe protozoan genus Plasmodium is responsible for malaria and has four medically important species: Plasmodium falciparum Plasmodium vivaxPlasmodium Malariae Plasmodium ovaleThe most vicious of these is P. falciparum because it is rapidly fatal and is responsible for most malaria related deaths. Mosquito-transmitted malaria is the greatest public health problem in large parts of the world with more than 500 million clinical cases and over 3 million deaths every year, mostly in African children under five years.Every 20 seconds, a child dies of malaria.Malaria occurs in most of the tropics of the world with P. falciparum predominating in subSaharan Africa through to New Guinea. P. vivax is more common on the Indian subcontinent, in Mexico & in Central America with the prevalence of falciparum and vivax malarias being about the same in Asia, Oceania and South America. Infrequent P. malariae is found in most endemic areas, especially subSaharan Africa that has also 90 % of the deaths. P. ovale is unusual outside Africa, although it can be found in southern India. Also, malaria can be a travelers disease and imported into any country.By 1970 malaria eradication had succeeded with DDT in all Europe. Malaria used to be prevalent in Russia, USA & Canada. It was prevalent around the Mediterranean, Italy, Greece, Yugoslavia, Bulgaria, Turkey and southern Britain. It had also been eradicated in Russia, North America, several middle eastern countries, large parts of South America, the Caribbean, Australia, Japan and Taiwan.

Group 1: A: Countries which have eliminated malaria: Bahrain, Jordan, Kuwait, Lebanon, Libyan Jamahiriya, Palestine, Qatar, Tunisia, United Arab EmiratesB: Countries with very limited malaria transmission in residual foci: Egypt, Morocco, Oman and Syrian Arab Republic

Group 2: Countries with low malaria burden limited to certain areas and with effective malaria programmes: Islamic Republic of Iran, Iraq and Saudi Arabia

Group 3: Countries with moderate/ high malaria burden, weak health system and/or complex emergencies: Afghanistan, Djibouti, Pakistan, Somalia, Sudan, Yemen

Malaria has always had a greater impact on humans than any other parasite or infectious agent. Malaria is a rural disease due to the presence of the female Anopheles mosquito vector. Can mosquito vector transmission be lowered? How? In 1956 the World Health Organization (WHO) began a global malaria eradication program, mainly because of the effectiveness of DTT in killing the mosquito vectors. This is an incredibly good pesticide, cheap to make, long-lasting and apparently harmless to humans!

One biological reason for the defeat was the development of some resistance to pesticides by the vectors, and another was the development of some drug resistance by the parasite itself. But . . . When health authorities do not have the money or have the will to spend it on vector control, they often lie and promote underestimates of the threat.Transgenic mosquitoes incompetent to transmit the sporozoites are a bright shiny hope.How is global malaria to be managed? Who pays the bill? Political will, public health education and similar social factors sometimes centering on poverty shape the WHO campaign for eradication. Global eradication as an ideal may be impossible for fault of gigantic financing, yet the eradication of malaria is long overdue in countries, not willing to spend the money. Many populations across the world have no idea of the health threats that they live under.In India 75 million cases in 1950 were down to 100,000 cases by 1970. Transmission rates in Africa and India were severely reduced. Malaria had been almost eliminated in Sri-Lanka. All of this progress was lost because of DDT hysteria. The enormous penalty for hysteria and mendacity includes losing control of filariasis. Still, the WHO did know what would happen if DDT was suspended. Mendacity is exhibited by crying about drug resistance, while not honestly discussing or otherwise even mentioning lifesaving DDT. Affluent countries without malaria decided to ban DDT whose main features are low cost and efficient residual effect. The vector life cycle

All four species are transmitted through: The bite of an infected female Anopheles species mosquito. Malaria also can be transmitted via a blood transfusion or congenitally between mother and fetus. Malaria-carrying Anopheles mosquitoes tend to bite only near dusk and dawn. The vector, the Anopheles species mosquito, passes plasmodia, which are contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating RBCs and feed on the hemoglobin, other proteins and glucose within the cells.

Insect life cycles are well known: eggs, pupas, larvas and adults. Anopheles mosquitoes feeding on infected hosts ingest sexual forms developing in RBCs. The female macrogametocytes and male microgametocytes mature in the mosquitos stomach and combine forming a zygote. Over 5-10 hours, the zygote in the mosquito differentiates into a cigar-shaped invasive ookinete. During the differentiation of the ookinete the diploid set of chromosomes divides as the first step in a two stage meiosis, the second stage takes place at the start of sporogony. The ookinetes force themselves between the epithelial cells to the outer surface of the mosquito stomach, and form into small spheres called oocysts. The oocysts enlarge as the nucleus divides, eventually rupturing and releasing thousands of motile sporozoites into the body cavity. The sporozoites migrate to the salivary glands, making the female mosquito infective. The vector phase of the life cycle, called sporogony, is complete in 8 to 35 days depending on species and environmental conditions.Development time from egg to adult mosquito depends on species and temperature, ranging from 7 days at an average temperature of 31C, to 20 days at an average temperature of 20C. Average life span of a female mosquito under favorable conditions is about 2 weeks with some living 3-4 weeks. Females lay eggs 3-6 days after they emerge. Single blackish anopheline eggs of about 0.5 mm length air-filled floats that let them drift on the water surface. Eggs hatch 2-3 days after being laid. The larvas do not have the air tube or siphon found in other mosquito larvas. They float horizontally on the surface of the water, and after molting three times develop into pupas that emerge as adults after 2-4 days. Needing a blood meal for the development of their eggs, all female mosquitoes bite at less than 3 km from their breeding sites, but many live within just 30 m diameter from where they were born. Also note that anophelene mosqitoes are dusk and dawn biters like Aedes aegypti.How long does sporogony take in what conditions and in what vector hosts? How do such variables affect VECTOR COMPETENCE ?

The mammalian life cyclePlasmodia replicate inside the RBC. This replication induces RBC cytolysis and causes the release of toxic metabolic byproducts into the bloodstream. These symptoms include chills, headache, myalgia and malaise, occurring in cycles. The parasite also may cause splenomegaly, jaundice and anemia. The symptoms relate to blood cell destruction. P. falciparum may induce kidney failure, coma and death.Merozoite is the traditional term for vegetative or nonsexual state = trophozoite = schizont. A hepatic schizont contains many thousands of tiny, invasive merozoites, created in a single segmentation. These asexual merozoites are the smallest and shortest lived form of the life cycle. Within a few minutes, they invade RBCs. The apical complex of the merozite is specialized to recognise and attach to epitopes on the RBCsAll infected liver cells parasitized with P. falciparum and P. malariae rupture and release merozoites at about the same time. In contrast, P. vivax and P. ovale have two exoerythrocytic forms. The primary type develops, causes liver cell rupture, and releases merozoites just as in P. falciparum and P. malariae. The other form, which develops concurrently, is known as the hypnozoite. Sporozoites that enter liver cells differentiate into nonsexual hypnozoites that remain dormant for weeks, or even years. The hypnozoites activate and undergo exoerythrocytic schizogony, forming a wave of merozoites that cause a relapse. Relapses impede eradication attempts by causing unexpected local outbreaks. Of course, the vector must live long enough for sporogony to be completed if it is to become infective.Why are sporozoites so very important? Because they invade both mosquito salivary glands and human hepatocytes. Their invasiveness then makes them a target antigen.

Clinical symptoms Include the following: cough, fatigue, malaise, arthralgia, myalgia, and paroxysm of shaking chills and sweats. The classic paroxysm begins with a period of shivering and chills, which lasts for 1-2 hours followed by high fever.

Paroxyms of varying 48 hours belong to vivax, ovale and falciparum malaria, whereas 72 hours belongs to malariae infections. Clinical SymptomsMalaria is characterized by severe undulating fever (paroxyms) occurring every 48 or 72 hours, depending on the species, varying from 48 hours in P.vivax, P. ovale, and P. falciparum malaria, to 72 hours in P. malariae infections. The 48 hour fever is called tertian because it occurs every third day: fever on day 1, no fever on day 2, fever on day 3 and so on. The 72 hour fever is called quartan, because it returns on every fourth day.The erythrocytic schizogony cycle (vegetative) becomes synchronized, and the febrile paroxysms become consistent. Clinical Features of Malaria

P. vivax, P. falciparum P. Malariae P. ovale

Incubation 8-24 d 8-24 d 15-30 days

Type of fever Tertian Aperiodic Quartan quotidian TertianExoerythrocytic cycle Yes No No

Relapse Common Recrudescence RecrudescenceUncomplicated malariaFever and any of the following: Headache,Body and joint painsFeeling cold and sometimes shiveringLoss of appetite and sometimes abdominal painsDiarrhoea, nausea and vomitingSplenomegaly

Differential diagnosis for uncomplicated malaria Consider other illnesses, such as:Upper respiratory tract infection (Pharyngitis, tonsillitis, ear infection)pneumoniameaslesdengue influenza typhoid fever Remember that the patient may be suffering from more than one illness.SEVERE MALARIA Severe or complicated malaria definition:Fever and any of the following: Impaired consciousnessAnxiety, palpitation and sweatingConvulsions or fits with this feverFast or difficult breathingVomiting every feed / unable to feedPale hands, tongue and inner parts of the eyelidGeneralized body weaknessDehydrationJaundice Severe malnutritionDark urine or no urine

As many as 30% of nonimmune adults infected with P falciparum suffer acute renal failure, some with seizures. Blackwater fever is hemoglobinuria with the passage of dark-colored urine Noncardiogenic pulmonary edema is most common in pregnant women and results in death in 80% of patients. Profound hypoglycemia often occurs in young children and pregnant women. The most prominent symptoms all relate to loss of RBCs: a) tachycardia b) anemiac) feverd) hypotensione) splenomegalyThe principal signs of cerebral malaria are seizures and unconsciousness, usually preceded by a severe headache. Neurologic examination may include contracted or unequal pupils, a Babinski sign, and absent or exaggerated deep tendon reflexes. Cerebrospinal fluid examination shows increased pressure, increased protein, and minimal or no pleocytosis. High fever, 41 to 42C with hot, dry skin may occur. These symptoms of cerebral malaria are caused by microvascular obstruction that prevents the exchange of glucose and oxygen at the capillary level, hypoglycemia, lactic acidosis, and high-grade fever. These events impair brain function, yet rapid and full recovery most often follows prompt treatment.Renal failure, due to acute tubular necrosis, is a common complication of severe P. falciparum infections in nonimmune persons. The renal tubules can become clogged with hemoglobin and malarial pigment released during massive hemolysis, and microvascular obstruction can cause anoxia and glucose deprivation. An enlarged, tender spleen and a palpable liver was often present by the second week of infection.

Often fatal, acute pulmonary edema can develop rapidly and is associated with excessive intravenous fluid therapy. Fast, labored respiration, with shortness of breath, a non-productive cough, and physical findings of moist rales and rhonchi are usually present. Chest X-rays usually show increased bronchovascular markings. Most patients with falciparum malaria complain of loss of appetite and nausea. However, in some patients (especially young children), additional symptoms including vomiting, abdominal pain, watery diarrhea, and jaundice. Anemia is due to RBC destruction of all ages upon merozoite release as often seen in falciparum infections. P. vivax and P. ovale require young red blood cells (reticulocytes) and P. malariae requires mature blood cells for infection. Differential diagnosis for complicated malariaConsider other illnesses such as:Measles Meningitis Tonsillitis Dengue Otitis media Influenza PneumoniaTyphoid fever TuberculosisHypoglycemia

Laboratory identifications with Giemsa The heart of an eradication campaign is the thick blood film. Interest focuses on good Geimsa staining. You must be able to identify the gametocytes of the 4 species, but first find out if malaria parasites are present. Examine a thick Giemsa slide, especially if from a field survey. The hospital slide from a patient already diagnosed needs to be identified to the species level.Diagnosis by the polymerase chain reaction (PCR) can become routine in some laboratories, whereas in most the cost is prohibitive. Dipsticks for histidine-rich protein (HRP2) of P. falciparum are accurate, fast and cheap. Other simple immunological highlights may develop. Present rapid dipstick methods stand out.

Anti Malarial DrugsChloroquine is a 4-aminoquinoline.Amodiaquine is a Mannich base 4-aminoquinoline.Sulfadoxine is a slowly eliminated sulfonamide.Pyrimethamine is a diaminopyrimidine used in combination with a sulfonamide, usually sulfadoxine (Fansedar) or dapsone.Mefloquine is a 4-methanolquinoline and is related to quinine.Artemisinin and its derivativesArtemisinin, also known as qinghaosuArtemether is the methyl ether of dihydroartemisinin.Artesunate is the sodium salt of the hemisuccinate ester of artemisinin.Dihydroartemisinin is the main active metabolite of the artemisinin derivativesArtemotil, previously known as arteether, is the ethyl ether of artemisinin

Lumefantrine belongs to the aryl aminoalcohol group of antimalarials, which also includes quinine, mefloquine and halofantrine.Primaquine is an 8-aminoquinoline and is effective against intrahepatic forms of all types of malaria parasite.Atovaquone is a hydroxynaphthoquinoneProguanil is a biguanide compound.Chlorproguanil is a biguanide and is given as the hydrochloride salt.Dapsone is a sulfone.Quinine is an alkaloid derived from the bark of the Cinchona tree.tetracyclines are a group of antibioticsDoxycycline is a tetracycline derivativeClindamycin is a lincosamide antibiotic

Anti Malarial DrugsTreatment of Malaria1) P. vivax, P. ovale: Oral chloroquine 10 mg/kg (max. 600 mg) followed by 5 mg/kg (max. 300 mg) after 6, 24 and 48 hours Oral primaquine 15 mg/kg / day x 14 days to prevent relapse.2) P. falciparum: Chloroquine sensitive : As above. Chloroquine resistant : Pyrimethamine 25 mg + sulphadoxine 500 mg tablets - 3 tablets single dose for adults OR - Quinine sulphate 650 mg (10 mg/kg) salt orally TDS times 7 days, plus Tetracycline 250 mg QDS times 7 days Multidrug resistant :Mefloquine 15-25 mg/kg (max 1.5 g) single dose orally OR - Artesunate 200 mg on first day followed by 100 mg daily times 4 days.Severe falciparum malaria (including cerebral malaria): Quinine IV 10 mg/kg over 4 - 8 hours TDS times 7 days (oral therapy when possible) Quinine resistant cases :Artesunate 2 mg/kg IM followed by 10 mg/kg after 6 hours on first day, then daily times 4 days OR - Artemether 160 mg (3.2 mg/kg IM) on first day; 80 mg (1.6 mg/kg IM) on days 2 - 5 Supportive Therapy : IV fluids, blood transfusion, etc.Chemoprophylaxis: Usually chloroquine 300 mg base once weekly, starting 1 week before exposure. Alternatives: Mefloquine, 250 mg base weekly, starting 1 week before exposure. Doxycycline, 100 mg daily, starting 2 days before exposure Chloroquine, 300 mg base weekly, starting 1 week before exposure + proguanil 200 mg daily, starting 2 days before exposure Antimalarial combination therapyAntimalarial combination therapy is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. The concept is based on the potential of two or more simultaneously administered schizontocidal drugs with independent modes of action to improve therapeutic efficacy and also to delay the development of resistance to the individual components of the combination.The rationale for combining antimalarials with different modes of action is twofold: (1) the combination is often more effective.(2) in the rare event that a mutant parasite that is resistant to one of the drugs arises de novo during the course of the infection, the parasite will be killed by the other drug. This mutual protection is thought to prevent or delay the emergence of resistance.To realize the two advantages, the partner drugs in a combination must be independently effective. The possible disadvantages of combination treatments are the potential for increased risk of adverse effects and the increased cost.

Artemisinin-based combination therapy (ACT)

Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10 000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required. but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. The evidence of their superiority in comparison to monotherapies has been clearly documented.ACTs for uncomplicated falciparum malariaThe following ACTs are recommended:artemether-lumefantrineartesunate - amodiaquineartesunate + mefloquineartesunate + sulfadoxine-pyrimethaminedihydroartemisinin piperaquine*efficacy of ACTs depend on the efficacy of the partner medicineThe artemisinin derivatives (oral formulations) and partner medicines of ACTs should not be used as monotherapy in the treatment of uncomplicated malaria World Health Organization18 March, 201245

Defective globin genes. About 250 million people, 4.5 % of the world population, are carriers of a defective globulin gene. Each year about 300,000 homozygotes are born about equally divided between sickle cell disorders and thalassemia syndromes. Malarial parasites feed on RBCs. Then clinical symptoms like plain anemia and just about everything else are strongly affected by RBC destruction. Are there mutant hemoglobin molecules unsuitable to mosquitoes? Yes. One causes sickle cell anemia, and others cause - and -thalassemias. This causes abnormal RBCs that again confer resistance to malaria.Another associated genetic blood disease is glucose-6-phosphate dehydrogenase deficiency in RBCs. Only men are affected as this is an X-chromosome linked trait. Glucose-6-phosphate dehydrogenase is involved in protecting RBCs from damage by free radicals and in particular reactive oxygen intermediates.

The establishment of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) is providing significant new grants to help countries accelerate implementation of their plans to roll back malaria.