227.1 🎓 醫孞生版

227.1.0.1 📌 䞀頁重點

227.1.0.1.1 Species + Geography
  • 5 human species: P. falciparum (most severe), P. vivax (most prevalent globally, relapses), P. ovale (West + Central Africa, relapses), P. malariae (chronic), P. knowlesi (zoonotic from macaques, SE Asia — Borneo)
  • Geography:
    • Sub-Saharan Africa: 95% of global mortality (mostly P. falciparum)
    • South + SE Asia: mostly P. vivax + P. falciparum
    • Latin America: P. vivax > P. falciparum
    • Oceania: PNG + Solomon Islands + Vanuatu
227.1.0.1.2 Vector + Life Cycle
  • Anopheles mosquito (female only)
  • Mosquito bites → sporozoites injected into bloodstream → hepatocytes (intrahepatic asexual reproduction) → merozoites burst out → invade RBCs (erythrocytic cycle) → trophozoite → schizont → merozoites → rupture → fever cycle
  • P. vivax + P. ovale form hypnozoites in liver (latent → relapse weeks-months later)
227.1.0.1.3 Burden (WHO 2024)
  • 249 million cases + 608,000 deaths/yr (2022)
  • 95% in Africa
  • Children under 5: 80% of deaths in Africa
  • Pregnant women + 5 yr children priority
227.1.0.1.4 Clinical
  • Incubation: 7-30 days (longer for vivax/ovale due hypnozoites)
  • Classic paroxysm:
    • Cold stage: chills, rigors, severe headache
    • Hot stage: high fever, flushing, vomiting
    • Sweating stage: profuse sweat, defervescence
  • Periodicity:
    • P. vivax + ovale: tertian (q48h)
    • P. malariae: quartan (q72h)
    • P. falciparum: irregular
  • Severity (P. falciparum primarily):
    • Severe: cerebral malaria, severe anemia, ARDS, AKI, hypoglycemia, severe acidosis, jaundice, shock, DIC, hyperparasitemia (> 5% in non-immune)
    • Mortality: 20-50% untreated severe
227.1.0.1.5 Diagnosis
  • Thick + thin blood smears (Giemsa) — gold standard
    • Thick: detection (sensitive)
    • Thin: species ID + parasitemia level
  • Rapid Diagnostic Tests (RDTs):
    • PfHRP-2 (P. falciparum) + pLDH (pan-Plasmodium)
    • 15-minute results
    • WHO prequalified for endemic + emergency
  • PCR — definitive, sensitive, species ID
  • Repeat smears q12-24h × 3 if first negative + clinical suspicion
227.1.0.1.6 Treatment
227.1.0.1.6.1 Uncomplicated P. falciparum
  • Artemisinin Combination Therapy (ACT):
    • Artemether-lumefantrine (Coartem) — preferred
    • Dihydroartemisinin-piperaquine
    • Artesunate-amodiaquine
    • Atovaquone-proguanil
  • 3-day course
227.1.0.1.6.2 Severe Malaria
  • IV Artesunate 2.4 mg/kg at 0, 12, 24 h then daily until tolerating PO (then complete with oral ACT)
  • Drug of choice — superior to quinine (AQUAMAT trial: ↓ mortality 22% vs 39%)
  • Alternative if unavailable: IV quinine
  • ICU
  • Avoid steroid for cerebral malaria (worsens)
227.1.0.1.6.3 P. vivax / ovale
  • Chloroquine (if sensitive) or ACT for blood stage
  • PLUS Primaquine 30 mg/d × 14 d OR Tafenoquine 300 mg × 1 for radical cure (hypnozoites)
  • G6PD test required before primaquine/tafenoquine (severe hemolysis if deficient)
227.1.0.1.6.4 P. knowlesi
  • ACT (works); IV artesunate for severe
  • Can mimic P. malariae on smear
227.1.0.1.7 Prophylaxis (Travelers)
  • Atovaquone-Proguanil (Malarone) — daily, 1 day before to 7 days after
  • Doxycycline — daily, 1 day before to 4 wk after; cheap, photosensitivity + GI
  • Mefloquine — weekly, 2 wk before to 4 wk after; CNS side effects + contraindicated psych history
  • Chloroquine — limited to chloroquine-sensitive areas (Central America, Caribbean, Mid East — not most Africa, Asia)
  • Tafenoquine (Arakoda) — weekly prophylaxis (G6PD test required)
227.1.0.1.8 Vaccines
227.1.0.1.8.1 RTS,S/AS01 (Mosquirix, GSK)
  • WHO recommended 2021 for children in moderate-high transmission Africa
  • 4-dose schedule (5, 6, 7, 18 mo)
  • 36% reduction severe malaria; 30% deaths
  • 12 African countries adoption 2024+
227.1.0.1.8.2 R21/Matrix-M (Oxford + Serum Institute India)
  • WHO recommended 2023
  • More efficacious (75% reduction in severe disease)
  • Lower cost
  • Mass rollout 2024+ (Cameroon, Kenya, etc.)
  • Major step forward — Africa endemic countries large-scale
227.1.0.1.9 Resistance
  • Artemisinin resistance emerging in SE Asia (Cambodia + Vietnam + others) — kelch13 mutations
  • Chloroquine resistance widespread in P. falciparum
  • Most current ACTs still effective in Africa
  • Surveillance critical

227.1.0.2 1⃣ Plasmodium Species

227.1.0.2.1 P. falciparum
  • Most severe — major killer
  • Sub-Saharan Africa primary, also Asia + Oceania + Latin America
  • Causes cerebral malaria, severe anemia, ARDS, AKI
  • Rapid death possible (< 24 hr in severe cases)
  • No hypnozoite (no relapse, but can have recrudescence with inadequate treatment)
  • Knob-like protrusions on infected RBC cause cytoadherence + sequestration
227.1.0.2.2 P. vivax
  • Most prevalent globally
  • Less severe than P. falciparum but causes hypnozoites + relapses
  • South + SE Asia, Latin America
  • Africa rare due Duffy-negative RBCs in Africans
  • Hypnozoites in liver → relapses weeks-months later
  • Mostly mild but severe cases recognized increasingly
  • Chloroquine resistance increasing (PNG, Indonesia, Brazil)
227.1.0.2.3 P. ovale
  • Similar to vivax (relapses)
  • West + Central Africa
  • Less common
227.1.0.2.4 P. malariae
  • Chronic infection (years)
  • Mild but persistent
  • Nephrotic syndrome complication (immune complex GN, especially Africa)
  • Quartan periodicity (q72h)
  • No hypnozoite (no relapse, but persistent low-grade parasitemia)
227.1.0.2.5 P. knowlesi
  • Zoonotic from long-tailed macaques
  • SE Asia (Borneo, Malaysia, Indonesia, Philippines)
  • 24-hour cycle (fastest, unlike other Plasmodium)
  • Can be severe
  • Microscopy can mistake for P. malariae (similar morphology) → PCR for differentiation
  • Cases increasing
  • Treatment: ACT, IV artesunate for severe

227.1.0.3 2⃣ Life Cycle

227.1.0.3.1 Exoerythrocytic (Liver) Cycle
  1. Anopheles mosquito bite → sporozoites injected
  2. Sporozoites travel to liver → enter hepatocytes
  3. Asexual reproduction in hepatocytes
  4. Hepatocyte ruptures → merozoites released into blood
  5. P. vivax + ovale: some sporozoites become hypnozoites (dormant) → relapse months-years later
227.1.0.3.2 Erythrocytic Cycle
  1. Merozoites invade RBCs
  2. Trophozoite (ring form)
  3. Schizont (mature)
  4. Schizont ruptures → releases merozoites + pyrogenic substances → fever paroxysm
  5. Merozoites invade new RBCs → continued cycle
  6. Some become gametocytes (sexual forms) → ingested by mosquito → continued transmission
227.1.0.3.3 Mosquito Cycle
  1. Gametocytes ingested in blood meal
  2. Fertilization in mosquito gut → zygote → ookinete → oocyst
  3. Sporozoites released → salivary glands → bite next human
227.1.0.3.4 Cytoadherence + Sequestration (P. falciparum unique)
  • Parasitized RBCs express PfEMP1 + other adhesins
  • Adhere to endothelium → microvascular sequestration in brain, kidney, lung, GI
  • Cerebral malaria, ARDS, AKI

227.1.0.4 3⃣ Clinical

227.1.0.4.1 Mild / Uncomplicated
  • Classic paroxysm (synchronous cycles):
    • Cold stage (1-2 hr): chills, rigors, severe headache, malaise
    • Hot stage (2-6 hr): high fever 40-41°C, flushing, vomiting, tachycardia
    • Sweating stage (2-4 hr): profuse diaphoresis, defervescence, exhaustion
  • Periodicity:
    • P. vivax + ovale: tertian (q48h, day 1-3-5
)
    • P. malariae: quartan (q72h, day 1-4-7
)
    • P. falciparum: irregular (every 36-48 hr in synchrony)
    • P. knowlesi: q24h (fastest)
  • Synchronized cycles take days-weeks to establish in primary infection (so initial fever may be continuous)
  • Common: fever + headache + myalgia + fatigue + jaundice + hepatosplenomegaly + mild anemia
227.1.0.4.2 Severe Malaria (P. falciparum primarily)

Per WHO definition, severe malaria includes any of:

227.1.0.4.2.1 Clinical Features
  • Cerebral malaria: GCS < 11; impaired consciousness; coma; seizures
  • Severe anemia: Hb < 7 g/dL (adult) or < 5 g/dL (child)
  • Acute kidney injury: Cr > 3 mg/dL or oliguria
  • Acute pulmonary edema / ARDS
  • Severe metabolic acidosis: pH < 7.25 or bicarbonate < 15
  • Hypoglycemia: < 40 mg/dL
  • Shock: SBP < 80 (adult) or < 50 (child)
  • DIC + spontaneous bleeding
  • Jaundice: bilirubin > 3 mg/dL
  • Hemoglobinuria (“blackwater fever”)
  • Hyperparasitemia: > 5% in non-immune; > 10% in immune
227.1.0.4.2.2 Lab Features
  • Hyperparasitemia (mature trophozoites + schizonts on smear)
  • Lactic acidosis
  • Hypoglycemia
  • Severe coagulopathy
227.1.0.4.2.3 Mortality
  • 5% with treatment in low-income
  • 20-50% if untreated severe
  • Cerebral malaria: mortality 20-30%
227.1.0.4.3 Cerebral Malaria
  • GCS < 11 with parasitemia
  • Seizures common (especially children)
  • Retinal hemorrhages + retinal whitening characteristic
  • Sequestered parasites in cerebral microvasculature
  • ICP monitoring sometimes
  • No role for steroid (worsens; possibly increases mortality)
  • Supportive: anticonvulsants, glucose, fluids, dialysis, transfusion as needed
227.1.0.4.4 Pregnancy
  • More severe in primigravidae (no placental antigen immunity yet)
  • Placental sequestration → low birth weight, prematurity, stillbirth
  • Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine in endemic Africa
  • ACTs and IV artesunate safe (and indicated) in pregnancy
227.1.0.4.5 Pediatric
  • 80% of African malaria deaths in < 5 yr
  • Cerebral malaria, severe anemia
  • Convulsions
  • IV artesunate for severe
227.1.0.4.6 Special Forms
  • Blackwater fever: massive intravascular hemolysis + hemoglobinuria + AKI; severe; often quinine-induced
  • Algid malaria: rare; sepsis-like presentation with low body temp; secondary bacterial sepsis (gram-negatives)
  • Hyperreactive Malaria Splenomegaly: chronic exposure → massive splenomegaly + ↑ IgM

227.1.0.5 4⃣ Diagnosis

227.1.0.5.1 Thick + Thin Blood Smears (Giemsa)
  • Gold standard
  • Thick smear: lyse RBCs, concentrate parasites (sensitivity)
  • Thin smear: identify species + count parasitemia level
  • Repeat q12-24h × 3 if first negative + clinical suspicion
  • Parasitemia expressed as % of infected RBCs (severity marker)
  • Identify:
    • Ring forms (early)
    • Trophozoites
    • Schizonts (in P. malariae, P. knowlesi, P. vivax/ovale; rare in peripheral P. falciparum due sequestration)
    • Gametocytes (banana-shaped in P. falciparum diagnostic)
227.1.0.5.2 Rapid Diagnostic Tests (RDTs)
  • PfHRP-2 antigen — P. falciparum specific
  • pLDH — pan-Plasmodium (all species)
  • Lateral flow immunoassay, 15-30 min
  • WHO-prequalified for endemic + emergency
  • HRP-2 deletion strains emerging in Horn of Africa (false negative for P. falciparum)
227.1.0.5.3 PCR
  • Most sensitive + species-specific (especially P. knowlesi differentiation)
  • Reference labs
  • For mixed infections + sub-microscopic
227.1.0.5.4 Lab Findings
  • Anemia
  • Thrombocytopenia (very common — often disproportionate to anemia)
  • ↑ LDH (hemolysis)
  • ↑ Bilirubin (hemolysis)
  • ↑ Creatinine in severe
  • Lactic acidosis in severe
  • Hypoglycemia in severe (especially pregnancy, children)
227.1.0.5.5 Other
  • Stool / urine — not relevant
  • Lumbar puncture if differential includes meningitis

227.1.0.6 5⃣ Treatment

227.1.0.6.1 Uncomplicated P. falciparum
227.1.0.6.1.1 Artemisinin Combination Therapy (ACT) — First-Line
  • Artemether-Lumefantrine (Coartem) — 6-dose regimen over 3 days; gold standard
  • Dihydroartemisinin-Piperaquine — once daily × 3 d (longer post-treatment prophylactic effect)
  • Artesunate-Amodiaquine — once daily × 3 d (Africa)
  • Artesunate-Mefloquine — Asia
  • Atovaquone-Proguanil (Malarone) — for treatment + prophylaxis (more expensive)
227.1.0.6.1.2 Alternative (if ACT unavailable)
  • Quinine + doxycycline × 7 d (older, severe side effects)
  • Clindamycin + quinine (pregnancy)
227.1.0.6.2 Severe Malaria
227.1.0.6.2.1 IV Artesunate
  • Drug of Choice (AQUAMAT trial 2010: ↓ mortality 22% vs 39% with quinine)
  • 2.4 mg/kg IV at 0, 12, 24 hr, then daily
  • Continue until tolerating PO
  • Then complete with oral ACT × 3 days
  • Total min 24 hours IV artesunate
  • Side effect: delayed hemolysis weeks later (rare, monitor)
227.1.0.6.2.2 Alternatives
  • IV Quinine (or quinidine) — older, severe side effects (hypoglycemia, arrhythmia, cinchonism)
  • IM Artemether if IV unavailable
227.1.0.6.2.3 Supportive Care
  • ICU monitoring
  • Anticonvulsants for seizures (lorazepam, phenytoin)
  • IV fluids (cautious — avoid pulmonary edema; isotonic saline)
  • Dialysis for AKI
  • Transfusion for severe anemia
  • Glucose for hypoglycemia
  • Mechanical ventilation for ARDS
  • AVOID steroid (worsens cerebral malaria)
  • AVOID heparin for DIC alone
227.1.0.6.3 P. vivax / P. ovale
227.1.0.6.3.1 Acute Blood Stage
  • Chloroquine 1 g initial → 500 mg at 6, 24, 48 hr (chloroquine-sensitive regions)
  • ACT also effective + standard if chloroquine resistance suspected (PNG, Indonesia)
  • Hyperparasitemia P. vivax with severe disease: treat as severe malaria
227.1.0.6.3.2 Radical Cure (Hypnozoites)
  • Primaquine 30 mg PO qd × 14 d OR Tafenoquine 300 mg × 1
  • G6PD test required before either (severe hemolysis if deficient — must measure G6PD activity quantitatively, not just qualitative)
  • Pregnancy: contraindicated (fetal G6PD unknown)
  • Lactation: contraindicated for tafenoquine
  • Without radical cure: relapses
227.1.0.6.4 P. malariae
  • Chloroquine sensitive (all areas)
  • No relapses → no need for primaquine
  • Quinacrine historic
227.1.0.6.5 P. knowlesi
  • ACT for uncomplicated
  • IV artesunate for severe
  • 24-hour cycle → rapid progression
  • PCR for definitive diagnosis (microscopy mimics P. malariae)
227.1.0.6.6 Pregnancy
  • All trimesters: ACT safe (artemether-lumefantrine first-line)
  • Quinine + clindamycin alternative
  • IV artesunate for severe pregnancy malaria
  • No primaquine/tafenoquine in pregnancy (fetal G6PD unknown)
  • IPTp (sulfadoxine-pyrimethamine) in endemic Africa
227.1.0.6.7 Pediatric
  • ACT weight-based
  • IV artesunate weight-based for severe
  • Convulsion management
  • Glucose monitoring
227.1.0.6.8 Travel-Acquired
  • Same regimens as endemic countries
  • ID consultation
  • Pre-travel chemoprophylaxis (case-by-case selection)

227.1.0.7 6⃣ Prophylaxis (Travelers)

227.1.0.7.1 Drug Choice (CDC + Country-Specific)
227.1.0.7.1.1 Atovaquone-Proguanil (Malarone)
  • Daily, 1 day before to 7 days after travel
  • Few side effects (GI, headache)
  • Expensive
  • Pediatric: weight-based (5+ kg)
227.1.0.7.1.2 Doxycycline
  • Daily, 1 day before to 4 wk after
  • Cheap
  • Photosensitivity, GI
  • Contraindicated pregnancy + < 8 yr
227.1.0.7.1.3 Mefloquine
  • Weekly, 2 wk before to 4 wk after
  • CNS side effects (vivid dreams, depression, psychosis)
  • Contraindicated psychiatric history, seizure
  • Long half-life — useful for long travel
227.1.0.7.1.4 Chloroquine
  • Weekly
  • Only chloroquine-sensitive regions: Caribbean, Central America (W of Panama Canal), Mid East (parts), Korea
  • Most of world resistant (P. falciparum)
227.1.0.7.1.5 Tafenoquine (Arakoda)
  • Weekly
  • G6PD test required
  • For prophylaxis + radical cure of P. vivax
  • Single 200 mg dose 3 days before travel, then weekly
  • After return: terminal dose × 1 + 200 mg q week × 2
227.1.0.7.2 Personal Protection (Additional)
  • DEET 30% or picaridin 20% insect repellent
  • Long sleeves + pants at dusk
  • Permethrin-treated clothing
  • Bed nets (insecticide-treated)
  • Window screens
  • Air conditioning
227.1.0.7.3 Pregnancy + Travel
  • Avoid travel to malaria endemic when possible
  • If must: chloroquine or mefloquine (avoid doxycycline + atovaquone)
  • IV artesunate if pregnancy malaria

227.1.0.8 7⃣ Vaccines

227.1.0.8.1 RTS,S/AS01 (Mosquirix, GSK)
  • WHO recommended 2021 for children in moderate-high transmission Africa
  • Recombinant CSP (circumsporozoite protein) + AS01 adjuvant
  • 4-dose schedule: 5, 6, 7, 18 months
  • 36% reduction in severe malaria; 30% reduction in deaths (pediatric Africa)
  • 12 African countries adoption 2024+ (Ghana, Kenya, Malawi, etc.)
  • Cost-effective public health intervention
227.1.0.8.2 R21/Matrix-M (Oxford + Serum Institute India)
  • WHO recommended 2023
  • More efficacious (75% reduction in severe disease)
  • Lower cost than RTS,S
  • 3-dose primary + booster schedule
  • Mass rollout 2024+ (Cameroon, Kenya, multiple African countries)
  • Major step forward for African endemic countries
  • Game changer for malaria control + elimination strategy
227.1.0.8.3 Future
  • mRNA malaria vaccines in Phase 2
  • Whole-sporozoite vaccines (PfSPZ — Sanaria)
  • Pre-erythrocytic + blood-stage + transmission-blocking targets

227.1.0.9 8⃣ Resistance

227.1.0.9.1 Artemisinin Resistance
  • kelch13 mutations (most common)
  • SE Asia origin (Cambodia + Vietnam + Thailand + Myanmar)
  • Causing partial resistance — slower clearance
  • ACT failures rare so far
  • Spreading to Africa concerning (Rwanda + Eritrea + Uganda reports 2020+)
  • Surveillance critical
227.1.0.9.2 Chloroquine Resistance
  • Widespread P. falciparum
  • Increasingly P. vivax (PNG, Indonesia, Brazil)
  • Drives ACT requirement
227.1.0.9.3 Multi-Drug Resistance
  • Drug rotation + combination therapy
  • New drug development priority