MALARIA

It is a protozoan disease transmitted by the bite of infected anopheles’ mosquito. Four species of the
genus ‘plasmodium’—P. falciparum, P. vivax, P. ovale, P. malariae cause malarial infection in human.
Almost all deaths are caused by falciparum malaria.
PATHOGENESIS
Human infection begins with the bite of an infected female anopheles mosquito which introduces
plasmodium sporozoites during a blood meal. This sporozoites invade hepatic parenchymal cells and
begin asexual reproduction.
A single sporozoite produces 10000–30000 daughter merozoites. This merozoites invade RBC and
multiply producing 6–30 daughter merozoites within 48–72 hours.
When parasite density reaches 50/ml of blood usually the symptomatic stage begins.
In P. vivax and P. ovale a portion of intrahepatic forms remain dormant for a period of 6 weeks to a
year or longer which are called hypnozoites and cause relapse which is characteristic of this two
species. After entry into the bloodstream the merozoite rapidly invade RBC which is mediated by
attachment to specific RBC receptors. In case of P. vivax, the receptor is related to Duffy blood group
antigen—Fy a and Fy b. West African people who are Duffy negative are resistant to P. vivax malaria.
After a series of asexual cycle in falciparum and immediately after release from liver in vivax, ovale,
malariae species, some of the parasites develop morphologically distinct long-lived sexual forms
called gametocyte that can
transmit malaria to mosquito.
CHANGE IN RBC
P. vivax and P. ovale invade young RBC
P. malariae → invades older RBC
P. falciparum invades RBC of all age.
Parasite consume the globin part of hemoglobin and the heme is polymerized to biologically inert
hemozoin or malaria pigment.
Pathogenesis of falciparum malaria
In falciparum infection, membrane protuberance appears on RBC surface at the end of 1st day of
asexual cycle. This knob expresses a high molecular weight strain-specific adhesive protein (PfEMPI)
plasmodium falciparum extra membranous protein 1 that mediates attachment to receptor on
venule and capillary endothelium, an event termed as cytoadherence.
The parasitized RBC also adheres with the uninfected RBC to form agglutination. Cytoadherence,
rosetting which play the key role in the pathology of falciparum malaria. This cytoadherence makes
falciparum a fatal disease.
Epidemiology—Endemicity in an area is determined by parasitemia or palpable spleen rate in
children of 2–9 years
Hypo endemic—Parasitemia or palpable spleen in children of 2–9 years, <10% of population
Mesoendemic—Parasitemia or palpable spleen rate in children < 11–50% of population
Hyperendemic—Parasitemia or palpable spleen in children = 51–75% of population
Holoendemic—Parasitemia or palpable spleen in children >75% of population
Stable transmission—Frequent year-round infection
Unstable transmission—Infection is low, erratic or focal and full protective immunity is not acquired
The endothelial receptors that mediate the adhesion are ICAM-1 in brain, Chondroitin sulfate-B in
placenta and CD-36 in other organs
Sickle cell disease, thalassemia, G6PD deficiency confer protection against falciparum malaria.
CLINICAL FEATURES
Common symptom is fever but initial symptoms are—
• Lack of well-being
• Headache
• Fatigue
• Muscle ache
• Abdominal discomfort.
There is no neck rigidity/stiffness, photophobia like that of meningitis.
Nausea, vomiting and orthostatic hypotension is common.
The classical untreated chronic malaria paroxysms has three phases—cold phase, hot phase,
sweating phase.
Cold phase—In which fever spike with chill and rigor, occurs at 48–72 hours interval as in vivax.
Hot phase—Temperature usually rises to ≥105° and persists for 4–6 hours.
Sweating phase—Fever subsides with sweating. Patient is usually afebrile in-between the typical
paroxysms.
MANIFESTATION OF ACUTE SEVERE FALCIPARUM MALARIA
SIGNS
Major Manifestation
• Unarousable coma or cerebral malaria—Failure to respond appropriately to noxious stimulous or
coma persisting for more than 30 minutes after convulsions with deep labored breathing.
• Acidemia, pH <7.25
Plasma HCO3 <15 mmol/L. Plasma lactate >5 mmol/L.
• Severe normocytic normochromic anemia (Hb <5 g/dL)
Hematocrit <15%/Hemoglobin <5 g. Parasitemia >1 lac per ml.
• Renal failure—
 24 hours urine output <400 ml
 12 ml/kg in children
 Serum creatinine >3 mg/dL
• Pulmonary edema/ARDS— Noncardiogenic pulmonary oedema aggravated by hydration.
• Hypoglycemia—Glucose level <40 mg/dL.
• Hypotension—
SBP <50 mm in child
SBP <80 mm in adult
Core-skin temperature difference >10°C
• Bleeding due to DIC—
Hemorrhage from gum, nose GIT with presence of D-Dimer in blood.
• Convulsion— >2 generalized seizure/24 hours.
• Hemoglobinuria (Black-water fever)—Black, brown or red urine not associated with oxidant drug
or G6PD deficiency.
Minor manifestation
• Jaundice—Bilirubin >3 mg/dL
• Impair consciousness—Obtunded but arousable
• Extreme weakness—Inability to seat unaided
• Hyperparasitemia—Parasitemia >5% in nonimmune patient and >20% in any patient.
FEATURES INDICATING POOR PROGNOSIS IN FALCIPARUM MALARIA
Clinical
1. Marked agitation
2. Hyperventilation
3. Hypothermia
4. Bleeding
5. Deep coma
6. Repeated convulsion
7. Anuria
8. Shock.
Laboratory Features of Severe Falciparum Malaria
A. Biochemistry
1. Hypoglycemia <40 mg/dL
2. Hyperlactatemia >5 mmol/L
3. Acidosis pH <7.3
4. Bicarbonate <15 mmol/L
5. Serum creatinine >3 mg/dL
6. Serum bilirubin >3 mg/dL
7. AST, ALT >3 times of the normal.
B. Hematology
1. Total count >12000/cu mm
2. Hemoglobin <5 g/dL
3. Coagulopathy—
– Platelet <50,000/cu mm
– P-time >3 sec of control
– Diminished fibrinogen <200 mg/dL.
4. Parasitology
– Hyperparasitemia causing increased mortality when parasitised RBC >1 lac/ml.
– High mortality when parasitised RBC >5 lac/ml.
– >5% neutrophil with pigment.
– >20% of parasites are trophozoites and schizonts.

DIAGNOSIS OF MALARIA
1. Thick blood film—Stained by Giemsa or Romanowsky stain for identification of parasitemia
(sensitive 0.0001% parasitemia).
2. Thin blood film—Stained by Giemsa or Romanowsky stain for species identification.
3. PfHRP2 (plasmodium falciparum histidine-rich protein-2) dipstick test—Robust in expensive rapid
test, sensitivity similar or superior to thick film.
4. Plasmodium LDH dipstick or card test—Rapid test, sensitivity similar to thick film.
5. Microtube concentration method with acridine orange staining—Sensitivity superior to thick film
(0.001% parasitemia) ideal for screening large number of simple. Do not identify species and require
fluorescence microscopy.

CHRONIC COMPLICATIONS OF MALARIA

TROPICAL SPLENOMEGALY (HYPERREACTIVE MALARIAL SPLENOMEGALY—HMS)
Some patients exhibit abnormal immunologic response to repeated or chronic malarial infection.
Patient with HMS presents with abdominal mass and dragging sensation in LUQ due to huge
splenomegaly and occasional sharp abdominal pain suggesting peri splenitis.
Anemia, pancytopenia and hepatomegaly are also seen but parasite is not usually present in the
peripheral blood.
Vulnerability to respiratory and skin infection is increased in HMS and patient may die of sepsis. In
small percentage of cases, it may transform to malignant lymphoprolipherative disorder.
Patient with HMS should receive chemoprophylaxis against malaria.
QUARTAN MALARIAL NEPHROPATHY
Chronic repeated infection with P. malariae and other species may cause production of soluble
immune complex, which cause injury to renal glomeruli in a small proportion of patients resulting in
nephrotic syndrome.
The histologic appearance is that of membranoproliferative glomerulonephritis with splitting of
capillary basement membrane and subendothelial dense deposit on EM study. Course granular
pattern of deposit on the basement membrane with selective proteinuria carries a better prognosis
than fine granular deposits.
Quartan nephropathy responds poorly to treatment by antimalarial, glucocorticoid and cytotoxic
agents.
IMMUNE SUPPRESSION
Immune dysregulation caused by parasite malaria increases the chance of EBV—infection and
Burkitt’s lymphoma among children in Africa.

TREATMENT
Specific Measures
1. Artesunate—In case of severe malaria 2.4 mg/kg IM or IV × 6 days at 24 hours interval only the
second dose is 1.2 mg/kg at 12 hours.
a. Artesunate 4 mg/kg (oral) × 3 day + single dose of Sulphadoxine 25 mg/kg and pyrimethamine
1.25 mg/kg on 1st day.
b. Artesunate + Amodiaquine (4 mg + 10 mg/kg oral) od × 3 days.
c. Artesunate—4 mg/kg for 3 days post+ Mefloquine 25 mg/kg to prevent emergence of resistance
(15 mg/kg on 2nd day and 10 mg/kg on 3rd day.
2. Quinine—20 mg/kg IV dissolved in 10% dextrose as initial loading dose to be transfused over 4
hours in case of severe malaria followed by 10 mg/kg dissolved in 10% dextrose to be transfused
over 4 hours every 8 hourly for 7 days.
Quinine to be combined with— Tetracycline 4 mg/kg qid, or doxycycline 3 mg/kg od, or clindamycin
10 mg/kg bid for 7 days.
(Tetracycline or doxycycline should not be used in pregnancy and child).
3. Chloroquine— (For Chloroquine sensitive P. vivax, P. ovale, P. malaria). 10 mg base/kg on 1st day
and 2nd day then 5 mg base/kg on 3rd day.
Primaquine—0.25 mg/kg/day for 14 days for radical cure.
For P. falciparum malaria which have no extraerythrocytic phase but to eliminate gametocyte from
blood—primaquine 0.75 mg/kg (single dose).
4. Sulfadoxine-pyrimethamine— (25/1.25 mg/kg) single dose for adult).
5. Mefloquine— (Complications—headache and psychiatric disorder).
15 mg/kg on the 1st day followed by 10 mg/kg (8–12 hours later) for 2 days.
6. Artemether or Arteether are oil-based and given intramuscularly.
3.2 mg/kg IM for 3 days. Only the 2nd dose is 1.6 mg/kg at 12 hours.
7. Artemether-lumefantrine— (For uncomplicated malaria) adult >35 kg. Each tablet containing
artemether 80 mg and lumefantrine 480 mg—one tab twice daily for 3 days.
8. Atovaquone + Proguanil— (For uncomplicated malaria) (Each tablet containing atovaquone 250
mg and proguanil 100 mg.) Adult >40 kg—4 tab. daily for 3 days with food.

IMMEDIATE MANAGEMENT OF SEVERE MANIFESTATION AND COMPLICATIONS OFMALARIA

1. Coma
− Maintain airway.
− Intubate if necessary.
This immunologic process stimulates RE cell hyperplasia and clearance activity which eventually
produces:
a. Massive splenomegaly
b. Hepatomegaly
c. Marked elevation of serum IgM and malarial antibody
d. Hepatic sinusoidal lymphocytosis
e. Peripheral B-cell lymphocytosis (in Africa)
There is production of cytotoxic IgM antibody to CD8 and CD5 T-cell with increase in the ratio of
CD4: CD8 T-cell. it leads to
B-cell proliferation with production of IgM and cryoglobulin, producing immune complexes.
• Side effects—hypotension and arrhythmia, cinchonism (high tone hearing loss), nausea, vomiting,
dysphoria
− Nursing of comatose patient.
− Exclude other treatable causes of coma like hypoglycemia and bacterial meningitis.
− Avoid corticosteroid, adrenalin and heparin.
2. Convulsion
− Maintain airway.
− Treat promptly with lorazepam, phenytoin, phenobarbitone and midazolam.
3. Hyperpyrexia
− Tepid sponging
− Cooling blanket
− Antipyretics—Paracetamol.
4. Hypoglycemia
− Measure blood glucose. 50 ml 50% dextrose IV followed by continuous 10% dextrose infusion.
5. Severe anemia—Transfusion of fresh screened whole blood or packed cell.
6. Acute pulmonary edema
− Prop-up at 45°.
− Oxygen inhalation.
− Venesection to drain 50 ml of blood in the donor’s bag.
− Diuretic—Frusemide.
− Stop IV fluid.
− Intubate—start PEP/CPAP. Mode of ventilation.
− Hemofiltration.
7. Acute renal failure
− Exclude prerenal cause.
− Check fluid balance and urinary sodium. If urine output is inadequate despite fluid replacement
and BUN and creatinine rise, renal replacement therapy by hemodialysis or hemofiltration.
8. Spontaneous bleeding and DIC
− Blood transfusion/cryoprecipitate/fresh frozen plasma/platelet transfusion.
− Injection vitamin K—10 mg/day IV.
9. Metabolic acidosis
− Exclude and treat hypoglycemia, hypovolemia, gram-negative septicemia.
− Give oxygen.
10. Shock
− Exclude gram–negative septicemia by blood culture.
− Give prophylactic antimicrobials.
− Correct hemodynamic disturbances.
11. Aspiration pneumonia
− Give (appropriate) parenteral antimicrobials
− Frequent change of posture
− Oxygen
− Physiotherapy.
CHEMOPROPHYLAXIS AGAINST MALARIA
1. Chloroquine sensitive areas: Chloroquine base 300 mg once weekly or proguanil 100–200 mg od
(Chloroquine is safe in pregnancy).
2. Partial chloroquine resistance areas: Chloroquine + Proguanil.
3. High chloroquine resistant areas: Mefloquine 250 mg once weekly, or Doxycycline 100 mg daily, or
Tab. Malarone (atovaquone 250 + proguanil 100 mg one tablet daily.
All of these drugs are to be started 1–2 days prior to entering into malaria endemic zone and to be
continued for 2 weeks after return.