Malaria

Malaria

Malaria is a protozoan disease transmitted by the bite of female Anopheles mosquitoes. Most important of the parasitic diseases of humans, with transmission in 103 countries affecting more than 1 billion people and causing between 1 and 3 million deaths each year Four species of the genus Plasmodium cause nearly all malarial infections in humans : P. falciparum, P. vivax, P. ovale, and P. malariae Almost all deaths are caused by falciparum malaria.
2

Causative Agent

Malaria is caused by one of four species of the prototype plasmodium. Female Anopheles mosquitoes feed on human blood to obtain the protein they need to develop their eggs.

Epidemiologi

Malaria occurs throughout most of the tropical regions of the world Endemicity traditionally has been defined in terms of parasitemia rates or palpable-spleen

The Life Cycle of Plasmodium

i.

Mosquitoes transmit Plasmodium when they feed on an infected human host and absorb the parasites gametes. These fuse and develop in the mosquitos gut to form infective stages, which move to the mosquitos salivary glands. When the mosquito feeds again the infective stages pass out into the blood together with an anticoagulant in saliva. The parasites enter the red blood cells, where they multiply.
6

ii.

iii.

iv.

Patogenesis,patologi
Manusia mrpkan hospes perantara,sedang nyamuk mrpkan hospes definitif untk infeksi plasmodium. Sikluskehidupan aseksual(skizogoni)ditemukan pd manusia,sedang siklus kehidupan parasit yg seksual(sporogoni)ditemukan pd nyamuk. Dalam siklus aseksual,satu eritrsit yg terinfeksi akan menghasilkan 6-32 merozoit pd setiap kejadian sporulasi.

Patogenesis,patologi
Infeksi oleh plasmodium malariae mrpkan infeksi paling ringan,hanya eritrsit matang yg diserang;siklus aseksuqal berlangsung 72 jam;jadi baru setelah 72 jam timbul generasi baru(merozoit)yg akan menyerang eritrosit yg lain. Jumlah merozoitpun hanya 6-12 saja dari hasil sporulasi dlm satu eritrosit. Infeksi oleh Plasmodium falciparum mrpakan yg terberat ok parasit ini menyerang baik retikulosit eritrosit matang,skizogoni berlangsung cepat dlm 36-48 jam.

Patogenesis,patologi

Dari satu eritrosit dihasilkan banyak merozoit(20-32 merozoit).Juga terjadi perubahan fisik pd eritrosit yg tdk dijumpai pd infeksi oleh pasmodium lainnya yi eritrosit yg terinfeksi lebih mudah saling mlekat pd endotel kapiler,membentuk trombus(aglutinasi)eritrosit yg terinfeksi jadi lebih tipis,lebih besar diameternya dan mudah pecah di dalam sistem retikulo endotelial. Pada setiap adanya destruksi eritrsit timbul demam yg paroksismal peridik,ok reaksi alergi thdp zat pirogen yg terbebas pd wkt sporulasi perjalanan khas demam malaria. Demam malaria yg khas : stadium 1:dingin(frigoris)berlangsung 2060 mnt.Stadium 2:panas(febris) 1-4 jam,Stadium 3:berkeringat(sudoris)berlangsun 1-3 jam. Ketiga stadium berlangsung 3-4 jam kadang 6-12 jam lalu disusul periode tidak demam(apireksia).

Patogenesis,patologi

Juga terjadi vasokonstriksi disusul vasodilatasi,yg seirama dg rasa menggigil dan demam. Pada infeksi dg P.Falsiparum,vasodilatasi ini dpat disertai Hipotaensi Banyaknya eritrosit yg pecah,menimbulakan anemia. Pigmen malaria,(heozoria),akan diambil lekosit segmen dan monosit lalu di deposit kedalam trabekula dan pulpa merah limpa,dan sistem retikuloendotelial lainnya(hati,otak). Limpa akan membesar ok kongesti dan hiperplasi sistemretikuloendotelial. Pada infeksi dg P.Falsiparum,terdapat gangguan sirkulasi g berat,anemi berat. Komplikasi pernisiosa,yi hiperpireksi,malaria serebral,ikterus/hepatitis,nekrosis tubuler akut.

10

Life cycle of malaria

Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal 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 (intrahepatic or preerythrocytic schizogony or merogony), a single sporozoite eventually may produce 10,000 to more than 30,000 daughter merozoites discharging motile merozoites into the bloodstream and symptomatic stage of the infection begins.

11

Life cycle of malaria

In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain dormant for months to years before reproduction begins. These dormant forms, or hypnozoites, are the cause of the relapses that characterize infection with these two species.
12

Life cycle of malaria

After entry into the bloodstream, merozoites rapidly invade erythrocytes and become trophozoites. Attachment is mediated via a specific erythrocyte surface receptor. During the early stage of intraerythrocytic development, the small "ring forms" of the four parasitic species appear similar under light microscopy. As the trophozoites enlarge, species-specific characteristics become evident, pigment becomes visible, and the parasite assumes an irregular or ameboid shape.
13

Life cycle of malaria

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 (merogony) red cell ruptures to release 6 to 30 daughter merozoites, each capable of invading a new red cell and repeating the cycle.
14

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. After a series of asexual cycles (P. falciparum) or immediately (P. vivax, P. ovale, P. malariae), some of the parasites develop into morphologically distinct long-lived sexual forms (gametocytes) that can transmit malaria.

15

After being ingested in the blood meal of a biting female anopheline mosquito, the male and female gametocytes form a zygote in the insect's midgut. This zygote matures into an ookinete, which penetrates and encysts in the mosquito's gut wall. The resulting oocyst expands by asexual division until it bursts to liberate myriad motile sporozoites, which then migrate in the hemolymph to the salivary gland of the mosquito to await inoculation into another human at the next feeding.
16

Diagram of Malaria Infection

Infection is by mosquito bite

Infects liver, then blood cells

17

18

Lamina basalis

Masuk sirkulasi

- 1 jam

Ovale : tachisporozoit & bradisporozoit

2-10 hr

Pre-paten 10-30 ribu parasit anak

19

Pathogenesis

The vector, the Anopheles species mosquito, passes plasmodia, which is contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (RBCs) and feed on the hemoglobin and other proteins within the cells. This protozoan brood replicates inside the cell. This replication induces RBC cytolysis and causes the release of toxic metabolic byproducts into the bloodstream symptoms : chills, headache, myalgias, and malaise in a cyclic pattern. The parasite also may cause jaundice and anemia.
20

Pathogenesis

P falciparum, may induce kidney failure, coma, and death. P vivax and P ovale may produce a dormant form that persists in the liver

Malaria-causing Plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment termed hemozoin. The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs, suppression of hematopoiesis, and increased clearance of RBCs by the spleen, which leads to anemia. Over time, malaria infection also causes thrombocytopenia and hepatosplenomegaly.

21

The morbidity and mortality caused by P falciparum are increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P falciparum and its ability to cytoadhere. Infected RBC produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, leading to much of the damage injurred by the parasite.
22

CLINICAL FEATURES

Clinical symptoms include the following: Cough, Fatigue, Malaise, Shaking chills, Arthralgia, Myalgia, Paroxysm of fever, and sweats The classic paroxysm begins with a period of shivering and chills, which lasts for approximately 1-2 hours, and is followed by a high fever. Finally, the patient experiences excessive diaphoresis, and the body temperature of the patient drops to normal or below normal Less common symptoms include the following: Anorexia and lethargy Nausea and vomiting Diarrhea Headache

23

Laboratory examination

Giemsa-stained thick and thin peripheral blood smears These smears are the criterion standard for malaria detection and should be sent to the laboratory immediately, since malaria is a potentially life-threatening infection. When reading the smear, 200-300 oilimmersion fields should be examined (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia). Rapid diagnosis test PF test, ICT test, paracheck, OptiMAL

24

Manifestations of Severe Falciparum Malaria

Signs Unarousable coma/cerebral malaria Acidemia/acidosis Manifestations Failure to localize or respond appropriately to noxious stimuli; coma persisting for >30 min after generalized convulsion Arterial pH <7.25 or plasma bicarbonate level of <15 mmol/L; venous lactate level of >15 mmol/L manifests as labored deep breathing, often termed "respiratory distress"

Severe normochromic, normocytic anemia

Renal failure ARDS

Hematocrit of <15% or hemoglobin level of <50 g/L (<5 g/dL) with parasitemia level of >100,000/mL
Urine output (24 h) of <400 mL in adults or <12 mL/kg in children; no improvement with rehydration; serum creatinine level of >265 mmol/L (>3.0 mg/dL) Noncardiogenic pulmonary edema, often aggravated by overhydration

Hypoglycemia
Hypotension/shock Bleeding/disseminated intravascular coagulation

Plasma glucose level of <2.2 mmol/L (<40 mg/dL)

Systolic blood pressure of <50 mmHg in children 1-5 years or <80 mmHg in adults; core/skin temperature difference of >10C Significant bleeding and hemorrhage from the gums, nose, and gastrointestinal tract and/or evidence of disseminated intravascular coagulation

Convulsions
Hemoglobinuriaa Other Impaired consciousness Extreme weakness Hyperparasitemia Jaundice

More than two generalized seizures in 24 h

Macroscopic black, brown, or red urine; not associated with effects of oxidant drugs and red blood cell enzyme defects (such as G6PD deficiency) Obtunded but arousable Prostration Parasitemia level of >5% in nonimmune patients Serum bilirubin level of >50 mmol/L (>3.0 mg/dL)

a Hemoglobinuria may occur in uncomplicated malaria. NOTE: G6PD, glucose-6-phosphate dehydrogenase.

25

26

Differential Diagnosis
Typhoid

fever Dengue Fever URTI Leptospirosis

27

Recommended Therapeutic Doses of Antimalarial Drugs

Drug
Chloroquine

Uncomplicated Malaria (Oral)

10 mg of base/kg followed by 10 mg/kg at 24 h and 5 mg/kg at 48 h or by 5 mg/kg at 12, 24, and 36 h (total dose, 25 mg/kg); for P. vivax or P. ovale, primaquine (0.25 mg of base/kg per day for 14 daysc) added for radical cure 25/1.25 mg/kg, single oral dose (3 tablets for adults)

Severe Malariaa (Parenteral)

10 mg of base/kg by constant-rate infusion over 8 h followed by 15 mg/kg over 24 h or by 3.5 mg of base/kg by IM or SC injection every 6 h (total dose, 25 mg/kg)b

Sulfadoxine/pyrimet hamine

Mefloquine Quinine

15 mg/kg followed 8-12 h later by second dose of 10 mg/kg 10 mg of salt/kg q8h for 7 days combined with tetracyclined (4 mg/kg qid) or doxycycline (3 mg/kg once daily) or clindamycin (10 mg/kg bid) for 7 days

20 mg of salt/kg by IV infusion over 4 he followed by 10 mg/kg infused over 2-8 h every 8 h

10 mg of base/kg by constant-rate infusion over 1-2 h followed by 0.02 mg/kg per min, with 28 ECG monitoringf

Quinidine gluconate

Recommended Therapeutic Doses of Antimalarial Drugs

Drug Artesunate Uncomplicated Malaria (Oral) In combination with 25 mg of mefloquine/kg, 12 mg/kg given in divided doses over 3-5 days (e.g., 4 mg/kg for 3 days or 4 mg/kg followed by 2 mg/kg per day for 4 days); if used alone, give for 7 days (usually 4 mg/kg initially followed by 2 mg/kg daily) Same regimen as for artesunate Severe Malariaa (Parenteral) 2.4 mg/kg IV or IM stat followed by 1.2 mg/kg at 12 and 24 h and then daily

Artemether

3.2 mg/kg IM stat followed by 1.6 mg/kg per day

Atovaquoneproguanil

For adults >40 kg, each dose comprises 4 tablets (each containing atovaquone 250 mg and proguanil 100 mg) taken once daily for 3 days with food

Artemetherlumefantrine

For adults 35 kg, each dose comprises 4 tablets (each containing artemether 20 mg and lumefantrine 120 mg) at 0, 8, 24, and 48 h (semi-immunes) or at 0, 8, 24, 36, 48, and 60 h (nonimmunes) taken after food

29

Management of Severe Malaria

30

SUPPORTIVE MANAGEMENT C.M.

AIRWAY FLUID REQUIREMENT : HYDRATION / OVERHYDRATION CONVULSION : DIAZEPAM MONITORING GCS & VITAL SIGN LAB : FBC, GLUCOSE, PAR.COUNT, CREATININE, UREUM, BLOOD GAS, URINE S.G, SODIUM, POTASSIUM. PREVENT : SHOCK, SEPTICAEMIA, ACIDOSIS, ARDS, HYPOGLYCAEMIA, ASPIRATION, BEDSORES. CM:cerebral Mal TREAT HYPERPYREXIA 31 VOLUME URINE & CATHETERIZATION

SPECIFIC TREATMENT SEVERE MALARIA ( Anti Malaria)

PARENTERAL START IMMEDIATELY DOSAGE, WEIGHT THE PATIENT MONITORING RESPONSE SWITCHED TO ORAL WHEN POSSIBLE MONITORING SIDE EFFECTS

32

ANTI MALARIAL THERAPY FOR S.M

QUININE QUINIDINE CHLOROQUINE ARTEMISININ :

ARTESUNATE

: I.V/ I.M / SUPPOSITORIES ARTEMETHER : I.M ARTEMISININ SUPP

SM:Severe Malaria
33

RECOMMENDED DOSES OF ANTI MALARIAL DRUGS FOR TREATMENT OF SEVERE/CEREBRAL MALARIA

DRUGS Quinine SIDE EFFECTS Hypoglycemia, chinchonism, tinnitus, hearing impairment, nausea, dysphoria, vomiting, prolonged QT interval, dysrhythmias, hypotension

20 mg of dihydrochloride salt/kg by iv infusion over 4 hr, then after loading, followed by 10 mg/kg over 4 hr every 8 hr. Patients should not received quinine or mefloquine within last 24 hr Alternatively, 7 mg of salt/kg can be infused over a period of 30 min, followed by 10 mg salt/kg over a period of 4 hr, or 10 mg of salt/kg (500 mg for adult) by i.v infusion over 8 hr continously 3 x a day

34

RECOMMENDED DOSES OF ANTI MALARIAL DRUGS FOR TREATMENT OF SEVERE/CEREBRAL MALARIA

DRUGS
Artemeter

Artemisinin

Chloroquine

3.2 mg/kg im initially, followed by 1.6 mg/kg daily. Not to be given iv (1 amp = 80 mg) Suppositories, 10 mg/kg at 0 & 4 hr followed by 7 mg/kg at 24,36,48 & 60 hrs. 10 mg base/kg infusion at constant rate over 8 hrs followed by 15 mg/kg over 24 hrs, or 3.5 mg base/kg 6 hourly or 2.5 mg base/kg 4 hourly by im or sc injection. Total dose 25 mg base /kg

SIDE EFFECTS

Hypotensi on

35

Convulsions
I.v. diazepam 10 mg adult or rectal 0.51.0 mg/kg i.m paraldehyde o.1 mg/kg adult Repeated conv- chlormethiazol infussion 0.8 %, Phenytoin 5 mg/kg i.v. 20 minutes Fosphenytoin 7.5 mg/kg i.v 20 mnutes

36

HYPOGLYCAEMIA ( Bl. Sugar < 40 mg% )

Coma, 20 -50 ml 50% dextrose i.v. 5 10 minutes ( routine is not recommended ) Infussion 10 % dextrose ( children 5% dextrose) beware hyponatremia Hypoglycaemia may developed Day 1 --- 7 Pushed 50% dextrose if necessary Glucagon injection Via nasogastric , beware gastric distension In peritoneal dialysis, add glucose in dialysis fluid Somatostatin analoque octreotide (Sandostatin)
37