Malaria

Paludisme, Paludismo, Малария

 

Malaria is the world’s most important parasitic disease.

Distribution • Malaria-endemic countries - more than 100 countries in Africa, Asia, Oceania, South and Central America, some of the Caribes.Malaria-endemic countries are among the poorest in the world. • More than a third of the world’s population (about 2 billion people) live in malaria-endemic areas and 1 billion people are estimated to carry parasites at any one time. • In Africa alone, there are an estimated 200-450 million cases of fever in children with malaria each year.  

Mortality  • Annual malaria mortality range from 0.5 to 3 million people.

Malaria-related mortality is particularly difficult to measure because the symptoms of the disease are non-specific and most deaths occur at home.

• Despite global economic development, more people die from malaria nowadays than 40 years ago.

World situation • During the “eradication era”, half a century age, malaria was eliminated or effectively suppressed in many parts of the world, particularly subtropical regions.  • Malaria is now on the rise again; since it is appearing in areas where it had disappeared, it is classified by some as a re-emerging disease.• WHO dates: Malaria in Europe region - 10 countries: Тurkey, Аzerbaijan, Аrmenia, Таdjekistan, Grusia, Uzbekistan, Каzakhstan, Кyrgystan, Тurkmenistan, Russia • Use of ineffective drugs for a potentially lethal disease will inevitably result in an increase in mortality. Development of resistance to antimalarial drugs had resulted in a four to eight fold increase in mortality.

Etiology and pathogenesis

 

Four species of the genus Plasmodium cause nearly all infections in

humans. These are Plasmodium vivax, Plasmodium ovale,

Plasmodium malariae, and Plasmodium falciparum.

 P. falciparum predominates in Africa, New Guinea, and Haiti;

P. vivax is more common in Central America and the Indian

subcontinent. The prevalence of these two species is approximately

equal in South America, eastern Asia, and Oceania.

P. malariae is found in most endemic areas, especially throughout

sub-Saharan Africa, but is much less common.

P. ovale is relatively unusual outside Africa.

Plasmodium vivax – cause Vivax malaria/ Tertian malaria Plasmodium ovale – Ovale malaria/ Tertian ovale malaria Plasmodium falciparum – Falciparum malaria/ malaria tropica/ subtertian malignant malaria Plasmodium malariae – Malaria malariae/ Quartan malaria

Mode of transmission - transmissial, - hemotransfussial,

- inoculation, - tissue transplantation, - transplacental

Vector

Various species of anopheline mosquitoes

are definitive hosts of malarial parasites

•         An. Maculipenis,•         An. Superpictus, •         An. Elutus ets.

Bilogical Cycle of parasites

Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal 

  When the female mosquito bites an infected person, she draws into her stomach blood that may contain gametocytes – male end female.

• In mosquito glend of the developmental cycle depends not only on the species of Plasmodium, but on the particular mosquito host and the ambient temperature (more than 16ºC).

• These microscopic forms of the malarial parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction.

• By this amplification process (known as intrahepatic or prerythrocytic schizogony or merogony), a single sporozoite eventually produces thousands of daughter merozoites.

• The swollen liver cell eventually bursts, discharging motile merozoites into the bloodstream; at this point the symptomatic stage of the infection begins.

• These microscopic forms of the malarial parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction.

• By this amplification process (known as intrahepatic or prerythrocytic schizogony or merogony), a single sporozoite eventually produces thousands of daughter merozoites.

• By the end of the 48-h intraerythrocytic life cycle (72 h for P. malariae), the parasite has consumed nearly all the hemoglobin and grown to occupy most of the red cell. Multiple nuclear divisions take place (schizogony or merogony), and the red cell ruptures to release 6 to 30 daughter merozoites, each capable of invading a new red cell and repeating the cycle.

The disease in human beings is caused by the direct effects of red cell invasion and destruction by the asexual parasite and the host's reaction. During this process, some parasites develop into morphologically distinct sexual forms (gametocytes, still within the erythrocytes), which are long-lived.

• Thus the infected erythrocytes sequester inside the small blood vessels.

• At the same stage, these P. falciparum-infected red cells may also adhere to uninfected red cells to form rosettes. The processes of cytoadherence and rosetting are central to the pathogenesis of falciparum malaria. They result in the sequestration of red cells containing mature forms of the parasite in vital organs (particularly the brain and heart), where they interfere with microcirculatory flow and metabolism. only the younger ring forms of the asexual parasites are seen in the peripheral blood in falciparum malaria.

• In the other three "benign" malarias, sequestration does not occur, and all stages of the parasite's development are evident on peripheral blood smears. Whereas P. vivax, P. ovale, and P. malariae show a marked predilection for either old red cells or reticulocytes and produce a level of parasitemia seldom exceeding 2 percent, P. falciparum can invade erythrocytes of all ages and may be associated with very high levels of parasitemia.

Clinical features Incubating period - 9 до 60 days P. vivax – 10 - 21 days, 8–14 months (P. vivax hibernans)P. ovale – 11 - 16 daysP. falciparum – 9 - 16 days P. malariae – 28 - 60 days

The first symptoms of malaria are nonspecific – the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches, anorecia, subfebril period, in children diarrhea , followed by fever are all similar to the symptoms of a minor viral illness.

This Prodromal period is 3-5 days. In some instances, a prominence of headache, chest pain,

abdominal pain, arthralgia, myalgia, or diarrhea may suggest another diagnosis.

Clinical features 

Malarial paroxysm

1. Fever - trembelling, tachicardia (1/2 - 2 hours);

2. Febrile period - 38 - 41 С, 4-6 hours, nausea, headache, tahipnoea, myalgia, arthralgia, convulsions, lose consciousness

3. Sweating - after fast fall of temperature (1-2 h)

• Start of malarial fever - on day ( 09 - 15 h) - Ovale malaria - usually evening

• Periodicity: - 48 h – invasion with P. vivax и P.ovale- 36- 48 h, or every day – invasion with P. falciparum- 72 h – P. malariae• The classic malarial paroxysms, in which fever

spikes, chills, and rigors occur at regular intervals, suggest infection with P. vivax or P. ovale.

• The fever is irregular at first (that of falciparum malaria may never become regular). The temperature of nonimmune individuals and children often rises above 40ºC in conjunction with tachycardia and sometimes delirium.

• Liver enlargement – in first days of desease

• Splenic enlargement, mild jaundice may develop in patients with otherwise -uncomplicated falciparum malaria and usually resolves over 1 to 3 weeks.

Severe Falciparum malariaCerebral malaria

• Coma is a characteristic and ominous feature of falciparum malaria and, despite treatment, is associated with death rates of approximately 20 % among adults and 15 among children.

• - Cerebral malaria manifests as diffuse symmetric encephalopathy; focal neurologic signs are unusual.

• Cerebral malaria manifests as diffuse symmetric encephalopathy; focal neurologic signs are unusual. Although some passive resistance to head flexion may be detected, signs of meningeal irritation are lacking. Approximately 15 % of patients have retinal hemorrhages. Fewer than 5 % have significant bleeding

Convulsions usually generalized and often repeated, are common, particularly among children with cerebral malaria. Whereas adults rarely suffer neurologic sequelae, approximately 10 % of children surviving cerebral malaria especially those with hypoglycemia, severe anemia, repeated seizures, and deep coma have some residual neurologic deficit when they regain consciousness.

• Pulmonary Edema (Noncardiogenic) Adults with severe falciparum malaria may develop noncardiogenic pulmonary edema even after several days of antimalarial therapy. Mortality is over 80 %. This condition can be aggravated by overly vigorous administration of intravenous fluid.

  Renal Impairment Renal impairment is common among adults with severe falciparum malaria but rare among children. The pathogenesis of renal failure is unclear but may be related to parasitized-erythrocyte sequestration interfering with renal microcirculatory flow Mortality in the initial phase of hypercatabolic acute renal failure is high; in survivors, urine flow resumes in a median of 4 days, and serum creatinine levels return to normal in a mean of 17 days Dialysis considerably enhances the likelihood of a patient's survival.

• Hematologic Abnormalities Anemia results from accelerated red cell destruction and removal by the spleen in conjunction with ineffective erythropoiesis. In severe malaria in nonimmune individuals and in areas with unstable transmission, anemia can develop rapidly and transfusion is often required. In many areas of Africa, children may develop severe anemia due to repeated malarial infections. This is a common consequence of continued infection resulting from treatment with chloroquine (or other drugs) to which the parasites are resistant.

• In Pregnancy Falciparum malaria is an important cause of fetal death. In hyper- and holoendemic areas, malaria in primigravida and secundigravida is associated with infected mothers remain asymptomatic despite intense parasitization of the placenta due to sequestration of parasitized erythrocytes in the placental microcirculation.

• Congenital malaria occurs in fewer than 5 % of newborns whose mothers are infected and is related directly to the parasitic density in maternal blood and in the placenta.

• Malaria In Children Most of the estimated 1 to 3 million persons who die of falciparum malaria each year are young African children. Convulsions, coma, hypoglycemia, metabolic acidosis, and severe anemia are relatively common among children with severe malaria, whereas deep jaundice, acute renal failure, and acute pulmonary edema are unusual.

• Chronic complications of malaria  

• Tropical Splenomegaly (Hyperreactive Malarial Splenomegaly) Chronic or repeated malarial infections produce hypergammaglobulinemia; normochromic, normocytic anemia; and in certain situations splenomegaly.

• Some residents of malaria - endemic areas in tropical Africa and Asia exhibit an abnormal immunologic response to repeated infections that is characterized by massive splenomegaly, hepatomegaly marked elevations in serum titers of IgM and malarial antibody

• Quartan Malarial Nephropathy

Chronic or repeated infections with P. malariae may cause soluble immune-complex injury to

the renal glomeruli, resulting in the nephrotic syndrome. Other, unidentified factors must

contribute to this process since only a very small proportion of infected patients develop renal

disease.

• Recrudescens of malaria develops in:

• -         Patients with P. falciparum without radical Therapy

• -         Resistent P. falciparum to 4-AQ

• -         Patients with P. vivax and P. ovale without Primaquine Th

R Relapses are: short-time – after 1 month; late – after 2 or more mths

• Asimptomic carrier

DIAGNOSIS

• The diagnosis of malaria rests on the demonstration of asexual forms of the parasite in peripheral blood smears subjected to Romanovsky staining. Giemsa at pH 7.2 is preferred. 

• Both thin and thick blood smears should be examined.

• The level of parasitemia is expressed as the number of parasitized erythrocytes among 1000 cells. The relation between parasitemia and prognosis is complex; in general, patients with more than 105 parasites per microliter are at increased risk of dying, but nonimmune patients may die with much lower counts.

• A poor prognosis is indicated by a predominance of more mature P. falciparum parasites (i.e., more than 20 percent of parasites with visible pigment) or circulating schizonts in the peripheral blood film or by the presence of phagocytosed malarial pigment in more than 5% of neutrophils.

Laboratory Findings • Normochromic, normocytic anemia is usually

documented. • The leukocyte count is generally low to normal,

although it may be raised in very severe infections.• The platelet count is usually reduced to about 105 per

microliter. Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin

times and by especially severe thrombocytopenia • Findings in severe malaria may include metabolic

acidosis, • with low plasma concentrations of:• glucose, sodium, bicarbonate, calcium, phosphate, and

albumin together with elevations in lactate, blood urea creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin.

Treatment

1. Blood schizonticides 2. Tissue schizonticides of P. vivax и P. ovale3. Gametocyticides

1. Blood schizonticides1. 4-aminoquinolines (4-АQ):

diphosphates - Chloroquin, Arthrochin, Resochin, Delagil, Aralen sulphates - Nivaquin  

Chloroquine – total doses 25-30 mg./kg., 1,5 g. 3 days, 1 day - 0,900 g. (I-st dose 0,600 g., after 6-8 h 0,300 g.), 2 и 3-ти day – x 0,300 g. Children – total dose: 25 mg/kg, 1 days 10 mg/kg, after 6-8 h 5 mg/kg, 2 и 3-th day x 5 mg/kg.

2. Pyrimethamine (Tindurin, Daraprim) tb. 25 mg, 2 / day3. Sulfonamides - Sulfadoxin tb. 0,250 g, Sulfalene tb 0,250 g4. Quinoline methanols - Mefloquine (Lariam) tb 0,250 g5. Phenanthrine ethanols - Halfan (Halophantrin) 6. Antibiotics – Tetracycline, Doxycycline (Vibramycin)7. Combined medicine: • Fansidar (Sulfadoxin + Pyrimethamin) tb. 0,5 g. 3 tb. eднокр., • Fansimef (Sulfadoxin+Mefloquine+Pyrimethamine) tb.0,775 g, 3 tb. 8. Artemisin (Qinghaosu) 10 mg/kg, 3 days, Artemether, Paluther, Artesunat9. Sinthetic – Pyronaridine и др.

The drug of choice for treatment of Resistant falciparum malaria are:- Quinine (sulphuricum/dihydrochloricum ) tb.0,200 g. 600 mg every 8 ч., 7 days + Tetracycline 250 mg/6h, 7 days, Children- 10 mg/kg

every 8 h, 3-7 days;  - Mefloquin tb. 0,250 gr, 15 mg/kg. immune person and 25 mg/kg non-immune,

max. dose 1 g, in 2 dose after 6 h. Therapy in patients who are unable to take the oral drug: I.V. - Chloroquine (diphosphate или sulfate) 10 mg/kg в 10 ml/kg isotonic fluid

(or amp. 5% sol. Chloroquine diphosphate – 0,2 ml/kg), very slow - for 4 h, second dose 5 mg/kg after 8 h, total dose 25 mg/kg

I.M. - Chloroquine 2,5 mg/kg every 4 h or subcutan - 3,5 mg/kg every 6 h till total dose 25 mg/kg.

I.V. - Chininum dihydrochloridum amp 2 ml. 300 mg base in 1 ml in adults and children: 10 mg/kg in 10 ml/kg 5% Glucose for 4 h, second infussion after 8-12 h. In pregnancy – the risk to the fetus of severe falciparum malaria greatly outweighs the possible risk of quinine therapy

2. Tissue schizonticides of P. vivax и P. ovale (effective against tissue schisonts)

• 8-aminoquinolines (8-АQ) – Primaquine 15 mg / day, 14 days, per os; in G-6-PD deficient - 7,5 mg/kg/ week, 8 weeks

• in patients with deffisancy of G6PD develop intravasals hemolisis • Children > 1 years – 0,25 mg/kg/day, 14 days. 3. Gametocyticides - Primaquine for all species of human malarial paracites• Chloroquine and amodiaquine – effective against the gametocytes of p.

vivax, p. ovale, p. malariae but do not affect p. falciparum 

PREVENTION

 In most of the tropics, the eradication of malaria is

not feasible because of the widespread

distribution of Anopheles breeding sites, the

great number of infected persons, and

inadequacies in resources, infrastructure, and

control programs.

• Where is possible, the disease is contained by

judicious use of insecticides to kill the mosquito

vector, rapid diagnosis and appropriate patient

management, and administration of

chemoprophylaxis to high-risk groups.

• No safe, effective, long- acting vaccine is likely

to be available for general use in the near future.

Personal Protection Against malaria

• Simple measures to reduce the frequency of mosquito bites in malarious areas are very important. These measures include the avoidance of exposure to mosquitoes at their peak feeding times (usually dusk and dawn) and the use of insect repellents, suitable clothing, and insecticide-impregnated bed nets. Widespread use of bed nets, particularly those treated with permethrin (a residual pyrethroid), often reduces the incidence of malaria and has recently been shown to reduce mortality in western and eastern Africa.

• Antimalarial prophylaxis. Travelers should start taking antimalarial drugs at least 1 week before departure so that any untoward reactions can be detected and therapeutic antimalarial blood concentrations will be present when needed. Antimalarial prophylaxis should continue for 4 weeks after the traveler has left the endemic area.

• Mefloquine has become the antimalarial prophylactic agent of choice for much of the tropics because it is usually effective against multidrug-resistant falciparum malaria and is reasonably well tolerated.

• Chloroquine 300 mg, деца 5 mg/kg./week, 1 week before travel • Fansidar – 1 tb./ 1 week before travel, 4-6 weeks after coming back x 2 tb./2 weeks • Mefloquine - x 1 tb./ week for adults and children above 45 kg• Proguanil ( Paludrin ) tb. 100 mg. (in pregnancy) - 200 mg/day, in children: <1 years

-25 mg, 1-4 years - 50 mg, 5-8 years -100 mg, 9-14 years -150 mg/day• Pyrimethamine - 2 tb./ week