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MALARIA - Complete Study Notes (Exam Edition)

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1. INTRODUCTION & DEFINITION

"Humanity has but three great enemies: Fever, famine, and war; of these by far the greatest, by far the most terrible, is fever." - William Osler, 1896

• Nearly all deaths are caused by P. falciparum
• P. knowlesi and P. vivax can also occasionally cause severe illness
• Humans are the only natural reservoir

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2. LIFE CYCLE (Pathogenesis)

A. Hepatic (Pre-erythrocytic) Stage

1. Female Anopheles mosquito bites → injects sporozoites into bloodstream
2. Sporozoites travel to liver within minutes (bind via thrombospondin-related adhesive protein and circumsporozoite protein to hepatocyte proteoglycans)
3. Inside hepatocytes: differentiate into merozoites (one sporozoite produces 10,000-30,000 merozoites)
4. Infected hepatocytes rupture → merozoites released into bloodstream

Important: In P. vivax and P. ovale, some forms remain dormant as hypnozoites in the liver - causing relapses months to years later.

B. Erythrocytic Stage

1. Merozoites invade RBCs (bind via lectin-like molecule to sialidated glycophorin)
2. Inside RBCs: Merozoite → Ring form → Trophozoite → Schizont
3. P. falciparum schizonts express PfEMP1 (knob protein) - binds ICAM-1, VCAM-1, CD36 on endothelium → cytoadherence → microvascular obstruction
4. Some trophozoites → gametocytes (infective stage for mosquito)
5. Schizonts rupture → merozoites released → new cycle
6. Symptoms appear when parasitemia reaches ~50/μL (100 million parasites total)

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3. EPIDEMIOLOGY

• In 2022: 249 million cases in 85 malaria-endemic countries; 608,000 deaths (~1,660 deaths/day) - Harrison's 22E
• Two countries account for ~43% of deaths (DRC and Nigeria)
• Endemic in sub-Saharan Africa, South/Southeast Asia, Central & South America
• P. falciparum dominates Africa; P. vivax dominates South Asia and Latin America

• India has ~45 species of anopheline mosquitoes; major vectors:
  • Rural areas: Anopheles culicifacies (most important)
  • Urban areas: Anopheles stephensi
  • Others: An. fluviatilis, An. minimus, An. philippinensis, An. sundaicus, An. maculatus
• ~100 million fever cases screened annually in India

• Human Blood Index - proportion of female Anopheles with human blood in stomach
• Sporozoite Rate - % female anophelines with sporozoites in salivary glands
• Man-Biting Rate - average anopheline bites per person per day
• Inoculation Rate = Man-biting rate × Sporozoite rate

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4. INCUBATION PERIOD

• Short incubation (<21 days) rules out malaria in travelers with appropriate chemoprophylaxis
• Most travel-related cases present within 1 month of return

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5. CLINICAL FEATURES (Symptoms)

Classic Malarial Paroxysm (3 stages):

1. Cold Stage (Rigor): Sudden chills, shivering, goosebumps - lasts 15-60 min
2. Hot Stage (Fever): High fever 39-41°C, headache, vomiting, flushing - lasts 2-6 hours
3. Sweating Stage (Defervescence): Profuse sweating, temperature falls, patient exhausted

• Tertian (every 48 h): P. vivax, P. ovale, P. falciparum
• Quartan (every 72 h): P. malariae
• Daily (quotidian): P. knowlesi

Other Common Features:

• Headache, myalgia, malaise, fatigue
• Nausea, vomiting, abdominal pain
• Splenomegaly (chronic - "Bignami's spleen" or "tropical splenomegaly")
• Hepatomegaly (mild)
• Anemia (hemolytic)
• Jaundice

Severe Falciparum Malaria (WHO criteria - exam important!)

"Blackwater fever" = massive intravascular hemolysis + hemoglobinuria; historically associated with quinine use in P. falciparum infection.

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6. SCREENING & DIAGNOSIS

A. Microscopy (Gold Standard)

• Thick blood smear - screening (more sensitive, detects parasites at low density)
• Thin blood smear - species identification (morphology preserved)
• Stain: Leishman's, Giemsa, or Field's stain
• Examined at intervals of 6-12 hours (parasites may not be detectable in early infection)

B. Rapid Diagnostic Tests (RDTs)

• Detect parasite antigens (HRP-2 for P. falciparum; pLDH, aldolase for all species)
• Sensitivity ~90-95% for P. falciparum, lower for non-falciparum
• Advantage: results in 15-20 min; no microscope needed; field use

C. PCR (Molecular Methods)

• Most sensitive and specific
• Detects all species; identifies mixed infections and drug resistance markers
• Used in reference labs; not routine in field settings

D. Serology

• ELISA, IFAT - detect antibodies; useful for epidemiological surveys, blood bank screening
• Not useful for diagnosing acute infection (antibodies persist long after infection)

E. Other Lab Findings

• Thrombocytopenia (very common, almost universal)
• Normochromic normocytic anemia
• Elevated LDH, bilirubin (hemolysis)
• Elevated creatinine (severe disease)
• Hypoglycemia (especially in pregnancy, severe disease, quinine treatment)
• Blood cultures to rule out bacteremia (common co-infection)

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7. PREVENTION AND CONTROL

A. Personal Protection (Individual Level)

• Insecticide-treated bed nets (ITNs) / Long-lasting insecticidal nets (LLINs) - single most effective measure
• Repellents: DEET (20-50%) on exposed skin; permethrin on clothing
• Protective clothing: long-sleeved shirts, long trousers (especially dusk to dawn)
• Screened windows and doors
• Indoor Residual Spraying (IRS): DDT, malathion, pyrethroid insecticides sprayed on indoor walls

B. Chemoprophylaxis (for Travelers)

No chemoprophylactic regimen is 100% protective - mosquito avoidance is always essential.

C. Vector Control Strategies (India - National Programme)

• Case detection (passive + active surveillance)
• Early diagnosis and complete treatment
• Sentinel surveillance

• Indoor Residual Spraying (IRS)
• ITNs and LLINs
• Anti-larval measures (source reduction, larviciding)
• Biological control (Gambusia fish, Bacillus thuringiensis israelensis)

• Capacity building
• Behavioral change communication (BCC)
• Intersectoral collaboration
• Monitoring and Evaluation

D. Vaccine

• RTS,S/AS01 (Mosquirix) - first licensed malaria vaccine; WHO recommended for children in sub-Saharan Africa (2021); targets P. falciparum circumsporozoite protein; ~30-40% efficacy
• R21/Matrix-M - newer vaccine showing ~75% efficacy in trials; recommended by WHO in 2023
• No vaccine currently approved/available for travelers

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8. TREATMENT

A. Uncomplicated Malaria

• Chloroquine (first-line, where sensitive): 600 mg base stat, then 300 mg at 6h, then 300 mg daily × 2 days
• For P. vivax/ovale: add Primaquine 15 mg/day × 14 days (to eliminate hypnozoites/prevent relapse)
  • Check G6PD status before primaquine (causes hemolysis in G6PD deficiency)
• Note: Chloroquine resistance in P. vivax reported in parts of Indonesia and Papua New Guinea

• Artemisinin-Based Combination Therapy (ACT) - WHO recommended first-line in ALL endemic countries

India's National Programme: ACT-AL (Artemether-Lumefantrine) or ACT-SP (Artesunate + SP) depending on region.

Add single-dose Primaquine (0.25 mg base/kg) to all falciparum treatments as gametocytocide (safe even in G6PD deficiency at this single dose).

B. Severe Falciparum Malaria

• Switch to oral ACT as soon as patient can swallow
• If acquired from artemisinin-resistant area: give IV artesunate + quinine together

C. Supportive Treatment in Severe Malaria

• ICU care, frequent monitoring
• Treat hypoglycemia: IV dextrose
• Treat seizures: benzodiazepines
• Blood transfusion for severe anemia (Hb <7 g/dL)
• Renal dialysis for renal failure
• Antipyretics: paracetamol (avoid aspirin - risk of Reye's syndrome in children)
• Do NOT use steroids (harmful in cerebral malaria)
• Dexamethasone is contraindicated in cerebral malaria

D. Drug Resistance (Important for Exams)

• Chloroquine resistance in P. falciparum: mediated by Pfcrt gene mutation
• Artemisinin resistance: mediated by Pfkelch13 mutations (confirmed in SE Asia - Mekong region)
• Mefloquine resistance: Pfmdr1 gene amplification
• Piperaquine resistance: Pfpm1/Pfpm2 gene amplification

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9. QUICK EXAM MNEMONICS

• Falciparum (worst)
• Vivax (relapse - hypnozoites)
• Ovale (relapse - hypnozoites)
• Malariae (nephrotic syndrome)
• Knowlesi (daily fever, SE Asia)

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10. KEY EXAM FACTS (High-Yield Summary)

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