MALARIA

1. MALARIA

3. Lifecycle Sporozoites (infective stage of the parasites) • Are inoculated into subcutaneous capillaries as female mosquito takes a blood meal • 8-15 sporozoites injected; within 30-45 mins they disappear from blood • Some enter hepatocytes and others are cleared by phagocytes Pre-erythrocytic schizogony (form of asexual reproduction ) (hepatic or tissue phase) Liver  multiply asexually (6-15 days)  merozoites  swollen hepatocytes rupture  release merozoites in blood stream  invade erythrocytes (asymptomatic and constitutes the incubation period)

4. In P. vivax and P. Ovale, - some intrahepatic sporozoites do not develop immediately - remain dormant in liver for weeks, months or upto 5 years before reproduction begins - sleeping forms or hypnozoites are responsibe for relapse In P. falciparum and P. malariae, - no persistent pre erythocytic phase, relapse does not occur - they cause recrudescence of infection, due to persistent erythrocytic form

5. Erythrocyticschizogony Merozoites ↓ Invade erythrocytes ↓ Attachment mediated by specific erythrocyte surface receptors: - duffy blood group antigen (P.Vivax) - glycophorins (P. falciparum, vivax, ovale) * P. malariae invades mature erythrocytes - parasitemia (no. of infected erythrocytes) <2% * P. falciparum invades both immature and mature erythrocytes - parasitemia ~60%

6. Trophozoites – malarial parasite inside the RBC Early phase (<12 hrs.), trophozoites ↓ Ring forms ↓ Grows into irregular or ameboid form ↓ 36 hrs. after invasion, repeated nuclear division occurs (merogony) and erythrocytes burst to release 6-32 daughter merozoites ↓ Invade uninfected erythrocyte and cycle repeated C/F – depends upon the duration of erythrocytic cycles * in P. vivax, ovale & falciparum, paroxysms occur every 48 hrs. (tertian) * in P. malariae, paroxysms occur every 72 hrs. (quartan)

7. After erythrocytic schizogony, • Parasites differentiate into sexual forms known as gametocytes (appear 3-15 days) • Gametocytes: Microgametocytes (male) Macrogametocytes (female) Sporogony - development of the parasite in the mosquito - 8-35 days - development depends on external temperature, species & mosquito

8. Female mosquito ↓ Blood meal on an infected person ↓ Gametocytes are ingested ↓ Microgametocytes → divides into 4-8 ↓ Further development in stomach (midgut) of the mosquito ↓ Fertilization (stomach of mosquito) ↓ Zygote ↓ Ookinetes (18-24 hrs) ↓ penetrates the stomach wall Oocyst→ repeated nuclear division → sporozoites ↓ thousands of motile sporozoites into the coelomic cavity from where they migrate to the salivary glands of the mosquito ↓ Female mosquito (infected)

9. Immune response to Malarial parasite • Less cytokines production • Malarial parasite can eludes host immune system by its ability to express antigen on the erythrocytes surface that change during the course of infection • Newborns and infants are protected against malaria by * antibodies required transplacentally & thru breast milk * fetal Hb which retards the development of parasites • Severe malaria is rare in children with marasmus or kwashiorkor, because there is decreased growth of parasites

10. Pathophysiology • Only blood stage parasites are involved in the pathogenesis • Exo-erythrocytic stages, sporozoites, & gametocytes do not induce pathophysiological changes Cytokines • Suppress erythropoiesis • Inhibit gluconeogenesis Rupture of infected RBC ↓ Macrophages produce ↓ TNF, IL-1, IL-6, IL-16 ↓ Fever, malaise * At physiological levels cytokines might be beneficial by facilitating parasite killing

11. Cytoadherence, sequestration, rosetting * Pathogenesis of P. falciparum Cytoadherence: After 24-36 hrs of merozoites ↓ Infected erythrocytes become sticky and adhere to venular and capillary endothelium called cytoadherence ↓ Due to appearance of knob like projection consisting of histidine rich protein (HRP) Sequestration: • Occurs in venules of various organs (greatest in brain followed by heart, liver, kidneys and intestine) • Disappearance of infected erythrocytes containing mature forms of P. falciparum from circulation • Absent in peripheral blood smear

12. Rosetting: • Erythrocytes containing mature forms of P. falciparum also adhere to uninfected erythrocytes called rosetting • Promote cytoadherence ↓ reduce blood flow ↓ impaired microcirculation and dysfunction of various organ system Incubation period  shortest for P. falciparum  longest for P. malariae

13. Uncomplicated malaria Common to all 4 species • No distinctive feature of malaria in children fever may not follow any definite pattern and may be irregular, continuous, remittent or intermittent in nature • Typical malarial paroxysms consisting of: fever spikes, chills & rigors occurring at regular intervals are uncommon, particularly in children below 5 yrs. • Initial symptoms of malaria are nonspecific and include: anorexia, malaise, irritability, headache, myalgia and slight fever • As infection continues, child may develop: high fever, headache, vomiting, diarrhea, pallor, slight jaundice

14. Classical malarial paroxysm consists of Cold stage Hot stage Sweating stage Cold stage • Sudden rise of temperature • Feeling of intense cold (chills) • Prompting the need for warmth or cover • Shivering with or without teeth chattering (rigors) • Rigors last for 10-30 mins, may last for 90 mins • There is peripheral vasoconstriction & gooseflesh

15. Hot stage • feels hot • Fever becomes high grade • Sever headache, myalgia, vomiting, tachypnea, palpitation, delirium • Lasts for 2-6 hrs. Sweating stage • Drenching sweats • Rapid fall in temperature • Lasts for 2-3 hrs.

16. Severe and Complicated Malaria • Almost all severe morbidity and mortality in malaria is caused by P. falciparum • Due to its tendency to produce high parasitemia, cytoadherence, sequestration, rosetting, & antimalarial drug resistance • Manifestations include: • Cerebral malaria • Severe anemia (Hb < 5g/dL or hematocrit < 15%) • Acute renal failure • Pulmonary edema or ARDS • Hypoglycemia (blood glucose < 40 mg/dL) • Shock • Repeated generalized convulsions (>2 episodes/day) • Hemoglobinuria * 1 or more of the above features in the presence of asexual parasitemia defines severe malaria

17. Cerebral Malaria • Diffuse, symmetric encephalopathy • Sudden onset but maybe gradual • Child has high fever for a few days followed by seizures & coma, maybe pallor, jaundice or splenomegaly • Neurological signs are variable and include deep coma, variable muscle tone and tendon reflexes, absent abdominal reflexes Pathologically cerebral malaria is characterized by: • Blockage of capillaries & venules with erythrocytes containing mature forms of P. falciparum • Cerebral blood flow is increases in order to meet the metabolic requirements of sequestrated parasites and leads to elevated intracranial pressures • Coma • CSF  normal

18. Anemia – can lead to high output cardiac failure and sudden death • Primarily due to destruction of parasitized erythrocytes Other reasons, • Destruction of unparasitized erythrocytes by immune mechanism • Dyserythropoiesis • Increased splenic clearance of parasitized as well as unparasitized erythrocytes

19. Black Water Fever • Sudden and massive intravascular hemolysis, and the passage of coca-cola colored urine due to hemoglobinuria Black water urine can occur: 1. when G6PD deficient patients are given oxidant drugs regardless of whether they have malaria or not 2. when patients of G6PD deficiency develop malaria and receive quinine 3. when patients with normal G6PD levels receive quinine

20. Hypoglycemia • Cytokine induced suppression of gluconeogenesis and • Increased glucose consumption caused by • fever • Anaerobic glycolysis • Malarial parasite Algid malaria (algid =cold) • From secondary Gm –ve bacteremia and hypovolemia • Patients with severe malaria are vulnerable to bacterial infections due to transient immunosuppression, impaired macrophage function, or blockade of the reticuloendothelial system

21. Others: • Renal failure  caused by acute tubular necrosis following obstruction of renal microvasculature by sequestrated erythrocytes • Pulmonary edema  increased pulmonary capillary permeability • Jaundice  due to hemolysis, hepatic dysfunction, & cytokines • DIC  coagulation cascade by the parasitized erythrocytes and cytokines • Metabolic acidosis  failure of liver and kidney to clear lactate & lactate production by the parasite

22. Chronic complications of malaria: repeated malarial infections can causes chronic complications. - tropical splenomegaly syndrome - nephrotic syndrome - endomyocardial fibrosis * Relapses: P.vivax & ovale – upto 5 yrs after intial infection (produce hypnozoites) P. falciparum & malariae – NO relapse

23. Tropical splenomegaly syndrome (also known as hyper-reactive malarial splenomegaly) repeated malaria ↓ constant stimulation of reticuloendothelial system by circulating Ag-Ab complex results in the enlargement of liver & spleen Essential features: • Massive splenomegaly • Mild to moderate hepatomegaly • Elevated IgG and IgM malarial antibody levels • Kupffer cells hyperplasia; maybe, • Anemia • Leucopenia • Thrombocytopenia • Growth retardation * parasites absent in peripheral blood Treatment: chloroquin &/or proguanil for 1 year ( response within 3 months)

24. Diagnosis Peripheral blood smear: gold standard thick smear – for parasite detection thin smear – for species identification * thick smear 20-40 times more sensitive than thin (contains more blood) * timing of blood smears with fever spikes is less important than repeating it 2-3 times a day in order to make a diagnosis * single negative smear does not exclude malaria and repeated smears should be obtained in a clinically suspected case * P. falciparum: peripheral smear - ring forms and crescent shaped gametocytes - intense parasitemia Antigen detection: histidine rich protein Polymerase chain reaction Serology

25. Treatment (antimalarial chemotherapy for uncomplicated malaria) Chloroquine sensitive malaria chloroquine 10 mg/kg stat followed by 5 mg/kg at 6, 24 & 48 hrs. * repeat the dose if child vomits within 30 mins Chloroquine resistant malaria (P. falciparum) 1. quinine 10 mg/kg 3 times a day for 7 days 2. mefloquine 15 mg/kg stat followed by 10mg/kg 12 hrs later 3. pyrimethamine 1.25 mg/kg + sulfadoxine 25 mg/kg as a single dose orally 4. halofantrine 8 mg/kg orally every 6 hrs for 3 doses, repeat after 1 week

26. Chemotherapy for complicated & severe malaria • Quinine 20 mg/kg (loading dose */** dilted in 10 ml/kg of 5 % or 10 % dextrose IV over 4 hours, followed 8 hours after starting the loading dose with 10 mg/kg (maintenance dose) over 4 hour 8 hourly, until the child can swallow oral quinine *** 10 mg/kg 3 times a day to complete 7 days of treatment OR • Artensunate 2.4 mg/kg IV blus or IM (loading dose) followed by 1.2 mg/kg IV or IM at 12 hours and then once daily for 6 days

27. OR • Artemether 3.2 mg/kg IM (loading dose) followed by 1.6 mg/kg IM daily for 6 days *In areas of growing quinine resistance add tetracycline 6.25 mg/kg 4 times a day OR doxycycline 3 mg/kg oce a day for 7 days except for children below 8 years and pregnant women. **Loading should be omitted if the patient has reeived quinine or halofantrine or mefloquine in last 24 hours ***If parenteral therapy is needed for more than 48 hours reduce the maintenance dose of quinine by one half to one third (5-7 mg/kg/dose)

28. Supportive Therapy • Dehydration and shock should be corrected • Packed red cells are transfused for severe anemia • Fever (Paracetamol poisoning) • Acid base disturbances should be corrected • Hypoglycemia should be corrected • Exchange Transfusion (if parasitemia exceeds 5 %) • Diazepam, Phenobarbitone or phenytoin (seizure)

29. Treatment of Relapse • P. Vivax and • P. Ovale • Chloroquine followed by Primaquine 0.25 mg/kg orally per day for 14 days • Primaquine case severe hemolysis in G-6PD deficiency

30. Prophylaxis • Chloroquinine sensitive malaria : - • Cloroqunine ------- 5mg/kg weekly OR • Proguanil ---------- 3mg/kg daily • Chloroquinine resistant area : - • Mefloquine -------- 3.5 mg/kg weekly OR • Doxycycline ------- 2 mg/kg daily OR • Malarone ( Atovaquone + proguanil) ---- daily