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)

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

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%

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)

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

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)

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

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

* 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

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

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

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

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.

- 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

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

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

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 not2. when patients of G6PD deficiency develop malaria and receive quinine3. when patients with normal G6PD levels receive quinine

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

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

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

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)

Peripheral blood smear: gold standardthick smear – for parasite detectionthin 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

(antimalarial chemotherapy for uncomplicated malaria)

Chloroquine sensitive malariachloroquine 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 days2. mefloquine 15 mg/kg stat followed by

10mg/kg 12 hrs later3. pyrimethamine 1.25 mg/kg + sulfadoxine 25 mg/kg as a

single dose orally4. halofantrine 8 mg/kg orally every 6 hrs for 3 doses, repeat

after 1 week

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

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)

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)

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

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