MALARIA / MedUrgnt
MALARIA
Malaria (mal: bad: aria: air) is a febrile illness caused by several species of a protozoon belonging to the genus Plasmodium. Species are named according to the interval between the paroxysms of hot, cold and sweating stages. It is transmitted to man by infected female Anopheles mosquito that injects sporozoites into the host blood. The disease can be transmitted also by blood transfusion, contaminated syringes and transplacentally as a cause of congenital infection in newborns.
Plasmodium species that are known to transmit the disease include:
• P. falciparum : Malignant tertian malaria
• P. Ovale: Benign tertian malaria
• P. Vivax: Benign tertian malaria
• P. Malariae: Quartan malaria
Other rare species include P. cynoughii and P. knowilisi
Though it has been completely eradicated in Europe and North America, the disease is still prevalent in West, Central and East Africa (P.falciparum) and Middle East and East Asia (P. vivax). In Sudan P. falciparum is responsible for almost 90% of cases and is associated with the most serious complications. Endemicity of the disease is classified according to the rate of splenomegaly among children in the specific area. Classification of degree of endemicity
Classification Spleen rate in children (2 - 10 years old)
Hypoendemic 0 - 10%
Mesoendemic 11 - 50%
Hyperendemic Constantly over 50%
Holoendemic Constantly over 75%
LIFE-CYCLE
The female mosquito acquires live parasite when feeding on human blood containing the gametocytes. Development of the parasite takes 7-20 days in which the male gametocyte rapidly develops in the mosquito intestinal fluid extrudes several flagella forming a microgamete. This becomes a macrogamete which in turn fertilizes the female gamete forming a zygote. The zygote penetrates the stomach wall and develops beneath its lining to form oocyst. Thousands of sporozoites are then produced which are released when the cyst ruptures. They migrate to salivary glands and are then injected into the host's tissues when the mosquito takes another blood meal.
The sporozoites in human subjects rapidly disappear from the blood stream within the next 5-7 days where they are implanted within the hepatic cells and multiply. This phase is called the pre-erythrocytic phase forming liver schizont containing up to 40,000 merozoites. These, once more enter the blood, re-invade the liver cells or invade the erythrocytes where they begin an asexual cycle (erythrocytic phase).
At the beginning of this stage, they give the appearance of a (signet ring) and thus called ring form. As the parasite matures it divides by schizogony forming a large collection of (trophozoites) which form schizonts (large collection of dividing trophozoites that vary from 8 to 24 depending on the species). When the RBC's rupture the trophozoites are released to invade other red blood cells. This can then the shizogenic cycle or develop into gametocytes which are taken up by the mosquito during its feed and subsequently repeat the cycle.
The degree of infectivity in humans by the disease depends on a number of factors including the innoculum size of sporozoites and host factors that are related to the immunity and nutritional status. Those living in an endemic or hyperendemic regions seem to have some resistance to malaria attack as well as those suffering from G6PD and some hemoglobinopathies like sickle cell disease or trait who are particularly protected against cerebral malaria. It is worth mentioning that cellular mediated immunity plays no role in the prevention of falciparum malaria.
Malaria Recurrence: Recurrence of malaria can be classified as follows:
1- Recrudescence: Symptoms recur after a symptom-free period. It is caused by parasites surviving in the blood as a result of inadequate or ineffective treatment
2-Relapse: Symptoms reappear between 2-28 weeks in tropical zones and months to years in temperate zones. This is commonly seen in P.vivax and P. ovale (hypnozoite)
3-Reinfection: This occurs after elimination of the first infection and a new parasite is introduced (usually >2weeks after treatment). Reinfection cannot easily be differentiated from recrudescence.
ENDEMICITY OF MALARIA:
1. STABLE MALARIA occurs in communities where there are repeated Infections and populations that have a high degree of immunity in a hyperendemic situation.
2. UNSTABLE MALARIA occurs in regions where transmission is intermittent. The immunity varies in these communities, and epidemics are liable to occur.
Clinical manifestations
The disease presents with malaise, nausea, loss of appetite, vomiting and diarrhea, back pain, joint pain and headache. A rapid pulse and a degree of hypotension are found. In the acute attack, the spleen is usually large and tender and may rupture due to minor trauma in severe cases, Hepatomegaly may occur and jaundice commonly occurs in children.
In falciprum malaria, haemolysis occurs due to intermittent destruction of RBCs by activated complement components or due to rupture as part of the disease process. This may lead to severe anemia requiring blood transfusion particularly in children. Hypersplenism has a role by premature red cell destruction. This is not often severe in P. vivax. In falciparum malaria the schizonts containing red cells adhere to the linings of the capillaries in the brain, kidneys, liver, lungs and gut causing these vessels to become congested and the organs they supply, become anoxic. Additionally schizonts have the ability to release toxins that cause damage of these organs.
P. vivax and P.ovale tend to invade the reticulocyte cells while P. malaria attacks mature red blood cells and P. falciparum invades all cells. Vitamin deficiency may develop as the parasite competes with the host for nutritional needs. Anemia, anorexia, release of cytotoxin, histamine and kinins may lead acute to organ damage ending in renal failure or adrenal crisis. Malignant tertian malaria causes these and other serious complications and may lead to death. Rupture of RBCs together with the liberation of pigments and toxins leads to the initial signs of malaria which is divided into three stages: cold, hot and sweating.
The cold stage: in which the patient feels cold, starts to shiver, develops rigors, and the temperature rises to 40 degrees C. It is due to the release of pyrogens from the ruptured RBCs causing vasoconstriction. The stage is short and lasts about 15 minutes to one hour. A few cases may take longer periods. At this point, the skin is pale and clammy, the pulse fast and thready, and the blood pressure is often raised. Nausea and vomiting are common at this stage.
The hot stage: this may last for about 1 to 4 hours. The patient complains of posterior orbital headache and the temperature may rise to hyperpyrexia level (41.6 C). The skin becomes flushed, feels hot and dry. The blood pressure may fall, and the pulse becomes full and bounding and respiration is rapid. Nausea and vomiting persists, and the patient may complain of thirst. At this stage the patient becomes restless and excitable and may go into delirium.
The sweating stage: the temperature subsides slowly and the patient begins to feel comfortable for 1 to 4 hours. Sweating appears first at the temples and rapidly become more generalized. The patient usually falls into an exhausted sleep from which awakens fresh. Other features include hepatosplenomegaly which is due to the liberation of parasites and pigments that are engulfed by the reticuloendothelial cells.
Complications
Complications during the acute attack of P.vivax, P.ovale and P.malariae are uncommon. Infection of 5–10% of RBCs is seen in P. falciparum which has a high invasive power. This is seen more common in children at age 6 months to 3 years. The sludging of infected RBCs (secondary to high parasitaemia, cyto-adherence, sequestration and rosetting) in the capillaries of the brain, liver, kidneys, bone marrow and other sites leads to severe complications that include the following:
a) Cerebral malaria:
It is associated with an unarousable coma in the presence of peripheral parasitaemia and when other causes of encephalopathy have been excluded. It is due to production of toxins and blockage of cerebral vessels leading to ischemia and oedema of the brain which result in many physiological and neurological signs including abolishment of the deep tendon reflexes or exaggeration, neck stiffness, meningitis, convulsions, hyperpyrexia and death. Clinical presentation includes fever, vomiting, convulsions, decrease level of consciousness or coma, pallor, jaundice, decerebrate and decorticate postures, contracted or unequal pupils, retinal hemorrhages and variable muscle tone and reflexes. Among survivals, quadreparesis, cerebellar ataxia, extapyramidal defects or hemiplegia, monoplegia, aphasia and mental retardation may occur. The mortality rate of in untreated cases is 80°%. Neurological deficits are usually reversible if patients are adequately treated.
b) Hyperpyrexia
This is characterized by very high temperature (_>41.6 C) with cessation of sweating and hot and dry skin. Disorientation, coma and loss of sphincter control are common.
C) Gastro-intestinal Tract involvement
i) Bilious remittent fever
This condition presents with acute epigastric pain associated with remittent fever, nausea, bile-containing vomiting and diarrhea which is coffee-ground in color or contains fresh blood diarrhea develops early while tender hepatomegaly occurs around the second day accompanied with Jaundice . The urine is scanty in volume with granular and hyaline casts, albumin and globulin. Renal failure may develop associated with anuria and uremia.
Death that can occur in severe cases may be due to vascular collapse or acute hepatic failure. Hyper-parasitaemia and schizonts may be found in large numbers in the peripheral blood film.
ii) Dysenteric malaria
This is characterized by frequent passage of stools that contain blood mucus, epithelial cell, cellular debris and in some cases pus cells Tenesmus, nausea and vomiting are common, and there is usually a high remittent fever. A blood film will usually show heavy parasitaemia.
d) Choleric malaria
Choleric malaria presents with profuse watery diarrhea, nausea, vomiting, and progressive dehydration. The stools are mainly fluid and contain particles of feaces and small quantities of blood and mucus. There may be muscular cramps in the limbs and abdomen. The salt content of both the blood and urine is low, and shock or acute renal failure with anuria and a rising urea level may occur similar to cholera. The parasites are found in the peripheral blood in large numbers.
e) Algid malaria
The condition is due to a gram negative septicemia but not adrenal failure. The patient passes rapidly into medical shock which is frequently associated with coma. The eyes become sunken, and the skin inelastic, pale and covered with a clammy sweat. Although the skin feels cold, the rectal temperature is raised to 38 - 39 degrees C. The patient suffers from severe epigastric pain with persistent vomiting and a chloraemic diarrhea. Breathing becomes shallow, sluggish and sighing. The pulse is thin and thready and the blood pressure is quite low. There is often an acute reduction of the circulatory volume with evidence of haemoconcentration and heavy parasitaemia is found in the blood film.This condition could be fatal in untreated patients due to circulatory failure.
f) Blackwater fever:
This condition is mainly seen in patients who have had repeated attacks of malaria that are inadequately treated or suppressed by quinine and in patients who suffer from G6PD. Sudden and severe intravascular hemolysis leads to oliguria, nausea, vomiting, jaundice and shock. Blood pressure and temperature fall, and if untreated, renal failure ensues. Urine may contain hemoglobin, albumin, hyaline and granular casts and blood pigments.
g) Other complications
Include acute renal failure from glomerulonephritis or less commonly, pulmonary edema which is common in pregnant females. Hypoglycemia may occur due to poor intake, vomiting and inhibtion glucose release from glycogen stores in the liver.
TROPICAL SPLENOMEGALY SYNDROME
This is a syndrome which is related to chronic malaria and malaria endemicity. It is characterized by the presence of a huge spleen, enlarged liver, anemia, thrombocytopenia, neutropenia and susceptibility to infection without apparent cellular immunity defect. Investigations reveal high IgM malarial antibodies and lymphocytic infiltration of hepatic sinusoids. Microscopic section of spleen shows normal architecture with dilated sinusoids that contain erythrocytes, lymphocytes and macrophages. Malaria parasites and pigments are absent. Bone marrow is hypercellular. Splenic sequestration of RBCs and hemolytic anemia may occur. Treatment with prophylactic antimalarial drugs for a long time leads to regression of the splenic and liver size and a drop in the IgM antimalarial antibodies.
MALARIA IN CHILDREN
In Tropical areas, malaria is one of the most significant causes of morbidity and mortality in children. Its presentation depends on whether the child is suffering from a recent acute infection, from frequent reinfections, or a continued prolonged infection. The clinical manifestations of malaria attack may not show the classical pattern of cold, hot and sweating stages.
The clinical manifestations of malaria attack may include dullness, restlessness, loss of appetite and vomiting that may contain bile. There could be severe colicky pain, considerable wind and diarrhea. Hepatosplenomegaly and abdominal tenderness are commonly found. The skin becomes dry, cool and clammy, although the temperature may rise to 38-40°C. Fever may be continuous, intermittent or remittent. Rigors are uncommon, but convulsions and meningism may occur. Anemia is prevalent with Hb level of 5 g/l.There is rapid loss of weight and puffiness of the face. Growth retardation may follow and splenic rupture may lead to abdominal crises.
MALARIA IN PREGNANCY
is a common cause of premature labor and abortion, especially in the last months of gestation. The mother may die of malaria at birth if not treated and the parasite may cross the placenta affecting the fetus congenital malaria; causing abortion, IUGR, still birth and neonatal death) or acute cause malaria of the newborn at birth (within 10-30 days after birth and presents with fever, restlessness, drowsiness, pallor, jaundice, poor feeding, vomiting, diarrhea, cyanosis and Hepatosplenomegaly).
SEVERE MALARIA
WHO criteria for severe malaria:
The presence of one or more of the following clinical or laboratory features (in the presence of peripheral parasitaemia):
Clinical manifestations
1. Prostration
2. Impaired consciousness
3. Acidotic breathing
4. Multiple convulsions
5. Circular collapse
6. Pulmonary oedema
7. Abnormal bleeding
8. Jaundice
9. Haemoglobinuria
Laboratory tests
- Severe anemia
- Hypoglycemia
- Acidosis
- Hyperlactatemia
- renal impairment
- Hyperparasitemia
INDICATIONS OF POOR PROGNOSIS
A) Clinical:
1-Marked agitation
2-Repeated convulsions
3-Hemodynamic shock
4-Anuria
5-Hyperventilation
6-Deep coma
7-Hypothermia
B) Laboratory results indicating poor prognosis:
- Hyperparasitaemia (> 100,000/ul i.e. about 2% of cells are infected).
- >20% of parasites are pigment-containing trophozoites and schizonts (late stage).
- >5% of neutrophlis with visible pigment
- Hyperlactatemia
- Severe hypoglycemia
- Leucocytosis >12000/ul
- Severe anemia (PCV<15%)
- Acidosis High serum creatinine
- High serum bilirubin
- Coagulopathy decreased platelet count (<50000/ul), prolonged prothrombin time and Decreased fibrinogen (<200mg/dl).
LABORATORY DIAGNOSIS OF SEVERE MALARIA
severe malaria more than 20% of parasites are piament-contain trophozoites and schizonts (late stages) and 5% of neutrophils with visible pigment. The patient may have hypoglycemia, hyperlactatemia and acidosis. They may also have high serum creatinine and bilirubin, leukocytosis >12000/ul and severe anemia (PCV <15%) and abnormal bleeding and clotting profile including decreased platelet count (<50000/ul), prolonged prothrombin time and decreased fibrinogen level.
For detection of malaria in the blood, 2 blood films should be taken: thick and thin blood films. The thick film is for the rapid detection of the parasite and the thin is for a more detailed examination of the parasite and species. The stains used are Gemsa, Field stain or the Leishman stain. Other tests include ELISA and IHA which are complementary to the above but are not a substitute. Dipstick antigen capture tests (Paracheck, Malaria PF test, optimal test, Para Site F), Phagocyte malarial pigment test and quantitative Buffy Coat method (QBCe). Malaria PF. Test: Immunoassay Chromatographic Test (ICT) which is now commonly used, is a rapid qualitative, membrane based immunoassay for the detection of P.falciparum antigen in whole blood. Results should be taken with caution as they do not differtiate between recent or previous infections.
TREATMENT
Antimalarial drug
1Chloroquine:10mg/kg base first, then 5mg/kg after 6 hrs, then 5mg/kg/day for 2days more. There is no place for iv. chloroquine except in cases of cerebral malaria where IV infusion can be used. Chloroquine for IV infusion should be diluted as it may cause arrhythmias, ventricular fbrillation, hypotension, and death. IV Vials should not be used as an action. IM chloroquine has a special formulation which should be used instead. The injection form should be administered deep may cause sterile abscess and other complications. This drug is no longer used in the Sudan due to the emergence of resistant strains.2. Quinine: 20mg/kg loading dose, iv, then 10mg/kg every 8 hrs until oral therapy can be started, to continue for 7 – 10 days or orally as 30mg/kg/day in 3 divided doses for 3-7 days
3. Pyremethamine-sulfadoxine (Fasidar) as a single dose: 1/4 tablet for less than 1 year, 12 tablet for those aged 1-3 years, 1 tab for 4-8 years old children, 2 tabs for 9-14 years old and 3 tabs for older than 14 years.
4. Mefloquin: Single dose, 15 - 25 mg/kg 50
5. Artemisinin-based Combination Therapy (ACTS) (according to body weight):
i) Artemether + Lumefantrine (Coartem): Weight 5 - <15 kg: one table first, then one tablet after 8 hrs, then one tablet BID for 2 days. Weight 25 - <35kg: 3 tablets first, then 3 tablets after 8 hrs, then 3 tablets BID for 2 days. Weight >35kg: 4 tablet first, then 4 tablets after 8 hrs, then 4 tablets BID for 2 days.
ii) Artesunate tablets and suppositories: 5mg/kg BID first day, then 5mg/ kg/day for 4 more days iii) artesunate injections: 1.m/iv: 2.4mg/kg BID first day, then 2.4mg/kg/day for 6 more days
iv) Artemether injections: im: 1.6mg/kg BID first day, then 1.6mg/kg/day for 6 days more
v) Artesunate + Sulfadoxine + Pyremethamine (ASP)
Antibiotics - These are adjuvant to other anti-malarials and should not be given alone. They act on the mitochondria of the parasite but they are slow acting. Antibiotics that have antimalarial effects are: Tetracycline which augments the action of chloroquine, Clindamycin, Cotrimoxazole, Pyrimethamine and sulphasalaxole, and Gentamycin: have a very good anti-malarial action
Treatment of severe malaria
• Artesunate 2.4mg/kg iv/im at O hr, 12 hr, 24 hr and then once daily for 6 more days
• Quinine iv 20mg/kg as a loading dose, then 10mg/kg every 8 hrs in slow infusion over 4 hrs diluted in 5 – 10 ml/kg of Dextrose 5% solution or Normal Saline for 7-10 days
• Artemether IM 3.2mg/kg first and then 1.6mg/kg/day for 6 more days. 29. proubog yd bereitomapos
Treatment of complicated Falciprum infection:
• Quinine (10mg/kg): by IV infusion over 2-4 hours to prevent circulatory failure and encephalopathy. This is repeated every 12 hours.
• Transfusion of packed red cells in case of severe anemia • Frusemide or manitol infusion if the patient has oliguria to prevent development of renal failure.
• Exchange blood transfusion if more than 10% of red blood cells are infected.
SIDE EFFECTS OF ANTIMALARIAL DRUGS
1-choroquin
Nausea, vomiting, damage to retina, ventricular fibrillation, arrhythmias, hypotension, dizziness, impairment hearing, psychosis, convulsions, peripheral neuropathy, proximal myopathy, bleaching of hair, photosensitivity, lichenplanus, hemolysis in G6PD deficiency.
2-Quinine
Nausea, vomiting, hypoglycemia, Cinchonism (tinnitus, vertigo, blurring of vision, ataxia, scotoma, deafness), blackwater fever, oxytocin-like effect thrombocytopenia and agranulocytosis
3-Pyremethamine
Skin rash, urticaria, Stephen-Johnson Syndrome, bone marrow depression sulfadoxine hemolysis in G6PD deficiency
4-Proguanil
Nausea, vomiting, haematuria, hair loss, mouth ulcers
5-Primaquin
Nausea, vomiting, hemolysis in G6PD deficiency, methaemoglobinaemia,
neutropenia
6-Mefloquin
Nausea, vomiting, epigastric pain, diarrhea, extrasystoles, syncope, neuropsychosis
7-Halofantrin
Diarrhea, skin rash, prolonged QT interval, ventricular arrhythmias
8-Artemisinin
Nausea, vomiting, pruritus
*It is the drug of choice now in resistant malaria because it is a schizontocidal to all species. Recrudescence is common when artemisinin is used alone; Therefore they are used in combination with other drugs eg Artemether+lumefantrine (Co-artem), Artesunate+meflaquin, Arte sunate+sulfadoxine+pyremethamine (ASP), Artesunate+Amodioquin, Dihydroartemesinin+ Pipraquin (Artekin), Artesunate+ Cholroproguaniles+Artesunate+ Dapatioquine .
PROPHYLAXIS
For prophylaxis of non-immune individuals, administration of antimalarial drugs should start one week before entering an endemic area and continued for at least one month after leaving the area. Proguanil, pyremethamine and chloroquine can be used as a once/ week dose. Pyremethamine is secreted in breast milk in an amount sufficient enough to protect the breast-fed baby for the first 3 months of life.
PREVENTION OF MALARIA
This can be achieved by controlling the reservoir and the vector. This is accomplished by producing breaks in the life- cycle, destroying breeding places, spraying with repellant and proper treatment and education of patients. Other measures are the use of insecticide impregnated nets, proper clothing, spraying and improving the environment's sanitation to decrease the amount of mosquitoes around.
Vaccines: most of these are still in the stage of trial
1- Irradiated sporozoites. It needs a lot of infections to develop immunity.
2- Purified immunoglobulins
3- Pre erythrocyte vaccine (RISSI/ASO2): effective but short lived.
4- DNA-based vaccine: activates cellular immunity
5- Erythrocyte-stage vaccine is under trial in Australia
6-Transmission-blocking vaccine against games. This may protect the
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