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Malaria - Complete Overview

1. Epidemiology

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2. Causative Agents - The Plasmodium Species

• Robbins & Kumar Basic Pathology, p. 392

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3. Life Cycle & Pathogenesis

Step-by-step life cycle:

• Female Anopheles injects sporozoites into bloodstream while feeding
• Two sporozoite surface proteins - thrombospondin-related adhesive protein and circumsporozoite protein - bind to proteoglycans on hepatocytes

• Sporozoites enter hepatocytes and differentiate into merozoites (hepatic schizonts)
• Incubation period: 1-4 weeks
• Infected hepatocytes rupture, releasing merozoites into the bloodstream
• P. vivax and P. ovale can form dormant hypnozoites in the liver, which cause relapses months to years later

• A lectin-like molecule on the merozoite surface binds to sialylated glycophorin (a red cell transmembrane protein), allowing merozoite invasion into RBCs within a "digestive vacuole"
• Merozoites → ring trophozoites → trophozoites → two fates:
  • Some become gametocytes (sexual stage; infective to mosquitoes)
  • Most become schizonts, which express PfEMP1 in knob-like extensions on the RBC surface
• PfEMP1 binds to endothelial adhesion molecules: ICAM-1, VCAM-1, CD36 → parasitized RBCs are sequestered in capillary beds
• Schizonts rupture → new merozoites released → cycle repeats

• Gametocytes are ingested when a mosquito bites; fertilization and sporogony occur in the mosquito gut, producing sporozoites that migrate to the salivary glands
• Robbins & Kumar Basic Pathology, p. 392-393; Goldman-Cecil Medicine

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4. Pathophysiology of Disease

Fever Pattern

• Episodic shaking chills and fever coincide with mass release of merozoites from lysed RBCs
  • Every 24 hours: P. knowlesi
  • Every 48 hours: P. vivax, P. ovale, P. falciparum
  • Every 72 hours: P. malariae

Anemia

• Repeated cycles of RBC infection and destruction → hemolytic anemia
• A characteristic brown malarial pigment (hematin) derived from hemoglobin is released from ruptured RBCs and deposits in the spleen, liver, lymph nodes, and bone marrow

Splenomegaly & Hepatomegaly

• Activation of mononuclear phagocytes → marked hyperplasia → massive splenomegaly, occasional hepatomegaly
• Chronic malaria: hyperreactive malarial splenomegaly with hypersplenism

Cerebral Malaria (P. falciparum)

• PfEMP1-mediated sequestration of parasitized RBCs in cerebral capillaries → vascular engorgement and occlusion → altered consciousness, seizures, coma, death
• Most common severe complication in children

Cytoadherence in Pregnancy

• The placenta uniquely expresses chondroitin sulfate A in the intervillous space, which is targeted by surface proteins of infected erythrocytes → placental sequestration
• Results in inflammatory infiltrate, cytokine release, disordered angiogenesis → placental dysfunction → IUGR, preterm labour, stillbirth, low birth weight
• Robbins & Kumar Basic Pathology; Goldman-Cecil Medicine; Creasy & Resnik's Maternal-Fetal Medicine

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5. Clinical Features

Uncomplicated Malaria

• Fever (may be continuous early, then becomes paroxysmal and cyclical)
• Headache
• Chills and rigors
• Myalgia/arthralgia
• Nausea, vomiting, diarrhea
• Fatigue and malaise

Fever Stages (Classic Malaria Paroxysm)

1. Cold stage - intense chills, rigor (15-60 min)
2. Hot stage - high fever 39-41°C (2-6 hours)
3. Sweating stage - profuse sweating, temperature falls, exhaustion (2-4 hours)

Severe/Complicated Malaria (predominantly P. falciparum)

• Goldman-Cecil Medicine; Rosen's Emergency Medicine

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6. Diagnosis

Clinical

• High index of suspicion in anyone with fever + travel to/residence in endemic area
• Malaria fever pattern may be absent early; initial fever often continuous
• Travel history is essential (see Box 122.2 - Rosen's EM)

1. Thick Blood Smear (Gold Standard in endemic areas)

• Blood dried on slide, stained with Giemsa
• Identifies parasites; allows quantification (parasite density vs. leukocytes)
• Limitation: doesn't allow morphological characterisation of RBCs
• Needs trained microscopist

2. Thin Blood Smear (Preferred in non-endemic settings)

• Giemsa-stained; better morphological detail for species identification
• P. falciparum: ring-form trophozoites only (mature forms sequester in deep capillaries)
• P. vivax / P. ovale: enlarged RBCs with Schüffner dots
• P. malariae / P. knowlesi: elongate intraerythrocytic trophozoites
• P. falciparum gametocytes: characteristic crescent/banana shape

3. Rapid Diagnostic Tests (RDTs)

• Colorimetric antigen detection; minimal training required; results in minutes
• HRP2 (histidine-rich protein-2): P. falciparum only; long-lived antigen
  • Risk: P. falciparum lacking HRP2 gene increasingly reported (South America, Horn of Africa)
• Lactate dehydrogenase / Aldolase: all Plasmodium species
• Some combo tests identify both P. falciparum and other species simultaneously
• One test approved in the USA

4. Molecular Assays (PCR)

• Highly sensitive; genus- and species-specific primers
• Loop-mediated isothermal amplification (LAMP): practical in field settings
• Limitations: time, cost, uncertain significance of low-level parasitemia in endemic areas

5. Serology

• Identifies past infection only; not useful for acute diagnosis
• Goldman-Cecil Medicine

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7. Treatment

Uncomplicated Malaria

P. falciparum (and mixed infections)

P. vivax

• Chloroquine 25 mg/kg divided over 3 days (in chloroquine-sensitive areas)
• Primaquine 0.25 mg/kg/day × 14 days to eliminate hypnozoites and prevent relapse
  • Contraindicated in: G6PD deficiency (causes haemolysis), infants, pregnant women
  • Test for G6PD deficiency before prescribing

Mixed Infections

• Treat as per P. falciparum protocol

Severe/Complicated Malaria

• IV artesunate - standard of care; superior to quinine (confirmed in clinical trials); FDA-approved for severe malaria
• For settings where IV artesunate unavailable: IV quinine or IV quinidine
• Supportive care: airway management, seizure control, blood transfusion for severe anaemia, dialysis for renal failure, glucose for hypoglycaemia

Special Situations

Pregnancy

• Primaquine contraindicated throughout pregnancy
• ACT not recommended for infants <5 kg

Drug Resistance

• Artemisinin resistance: delayed parasite clearance, initially in SE Asia (Cambodia, Vietnam), now emerging in East Africa - major concern
• Resistance suspected if no clinical + parasitological response within 72 hours despite full treatment without vomiting → treat with quinine + tetracycline/doxycycline
• Katzung Basic & Clinical Pharmacology, 16th Ed; Goldman-Cecil Medicine; Park's Textbook of Preventive & Social Medicine

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8. Antimalarial Drug Pharmacology

Artemisinins (Artesunate, Artemether, Dihydroartemisinin)

• Mechanism: Iron-catalysed cleavage of endoperoxide bridge → free radical generation → kill parasites
• Action: Very rapidly acting blood schizonticides against all Plasmodium species; active against young (not mature) gametocytes; no effect on hepatic stages
• Half-life: 30-60 min (artesunate, DHA); 2-3 hr (artemether)
• All are rapidly metabolised to the active metabolite dihydroartemisinin
• Resistance: Kelch-13 mutations mediate delayed clearance

Chloroquine

• 4-aminoquinoline; concentrates in the parasite's food vacuole; inhibits haem polymerisation → toxic haem accumulation
• Widely resistant P. falciparum; still effective for P. vivax in most areas

Primaquine

• 8-aminoquinoline; active against hepatic hypnozoites (radical cure of vivax/ovale) and gametocytes
• Causes haemolytic anaemia in G6PD deficiency
• Contraindicated in pregnancy and infants

Mefloquine

• Blood schizonticide; neuropsychiatric adverse effects (vivid dreams, anxiety, psychosis)

Quinine/Quinidine

• Rapid-acting; used for severe malaria or resistance settings; causes hypoglycaemia (stimulates insulin secretion), cinchonism (tinnitus, vertigo, deafness)

Sulfadoxine-Pyrimethamine (SP)

• Antifolate combination; used in intermittent preventive therapy in pregnancy (IPTp); widespread resistance in P. falciparum
• Katzung Basic & Clinical Pharmacology, 16th Ed; Goodman & Gilman's Pharmacological Basis of Therapeutics

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9. Complications Summary

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10. Prevention

Personal Protection

• Insecticide-treated bed nets (ITNs) - most effective; Anopheles mosquitoes bite at dusk and overnight
• Indoor residual spraying (IRS) - insecticides on walls/ceilings
• Insect repellents (DEET-containing)
• Protective clothing (long sleeves, trousers at dusk/night)

Chemoprophylaxis (for travelers)

Intermittent Preventive Treatment (IPT)

• IPTp (in pregnancy): SP given at each antenatal visit from 2nd trimester; reduces maternal anaemia and LBW
• IPTi (in infants): SP given at routine immunisation contacts
• SMC (seasonal malaria chemoprevention in children): SP + amodiaquine monthly during high-transmission season
• Mass Drug Administration (MDA): for population-level burden reduction in high-transmission settings

Vaccines

• RTS,S/AS01 (Mosquirix): first approved malaria vaccine; targets P. falciparum circumsporozoite protein; provides partial protection (~30-40% efficacy); recommended by WHO for children in sub-Saharan Africa
• R21/Matrix-M: newer vaccine showing higher efficacy (~75-77%) in trials; WHO-approved 2023; being rolled out
• An encouraging development for reducing fatal cerebral malaria in children
• Robbins & Kumar Basic Pathology; Goldman-Cecil Medicine; WHO Malaria Guidelines August 2025

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11. Malaria in Special Populations

Pregnancy

• Increased risk of severe disease, especially in primigravidae in endemic areas
• Complications: severe anaemia, pulmonary oedema, seizures, coma, death
• Fetal complications: IUGR, LBW, preterm birth, miscarriage, stillbirth
• Mechanism: placental sequestration via CSA binding (unique to placenta)
• Prevention: IPTp (SP at each ANC visit from 16 weeks), ITNs
• Travel to malarious regions should be avoided if at all possible

Children

• Most vulnerable group; account for 75% of malaria deaths in Africa
• Cerebral malaria and severe anaemia are the leading killers
• ACTs are safe and effective; dose by weight

HIV Coinfection

• HIV disrupts acquired immunity to malaria → increased incidence and severity
• Acute malaria elevates HIV viral load
• Drug interactions between antiretrovirals and antimalarials

Travellers

• Non-immune; at high risk of severe disease
• Most falciparum malaria presents within 1-2 months of return from endemic areas
• Longer-stay travellers without prophylaxis at highest risk
• Goldman-Cecil Medicine; Creasy & Resnik's Maternal-Fetal Medicine; Rosen's Emergency Medicine

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Quick Reference: Key Facts

• Vector: Female Anopheles mosquito
• Worst species: P. falciparum (causes cerebral malaria, blackwater fever, highest mortality)
• Relapsing species: P. vivax, P. ovale (hypnozoites in liver)
• Gold standard diagnosis: Giemsa-stained thick blood smear
• First-line treatment: ACT (artemisinin-based combination therapy)
• Severe malaria treatment: IV artesunate
• Contraindicated in G6PD deficiency: Primaquine (and dapsone)
• Fever periodicity: 48 hrs (vivax/falciparum/ovale), 72 hrs (malariae), 24 hrs (knowlesi)
• Vaccine: RTS,S (Mosquirix) and R21/Matrix-M approved for children in Africa