Malaria

Quick Reference

Critical Alerts

• Plasmodium falciparum causes severe/cerebral malaria with mortality of 15-25% even with optimal treatment [1,2]
• Severe malaria is a medical emergency requiring immediate IV artesunate and ICU-level care
• Artesunate IV is superior to quinine for severe malaria, reducing mortality by 35% in adults and 23% in children [3,4]
• Parasitemia > 2% with any severity marker indicates severe disease requiring parenteral therapy
• Consider malaria in ANY febrile patient with travel to endemic areas in the past 12 months (up to 3 years for P. vivax/ovale)
• Single negative blood film does not exclude malaria - repeat testing at 12-24 hour intervals for up to 72 hours
• G6PD testing mandatory before primaquine to prevent life-threatening hemolysis

Key Diagnostics

• Thick blood smear: Detection (sensitivity > 95% at > 100 parasites/μL) [5]
• Thin blood smear: Species identification and parasitemia quantification [5]
• Rapid diagnostic test (RDT): HRP2 for P. falciparum, pLDH for all species (sensitivity 95-99%) [6]
• Parasitemia percentage: Light (less than 1%), moderate (1-4%), heavy (> 5%), critical (> 10%)
• CBC: Thrombocytopenia (80-90% of cases), hemolytic anemia
• BMP: Hypoglycemia, acute kidney injury, metabolic acidosis
• Lactate: Elevated lactate (> 5 mmol/L) predicts mortality in severe malaria [7]
• G6PD enzyme assay: Essential before primaquine administration

Emergency Treatments

• Severe malaria: IV Artesunate 2.4 mg/kg at 0, 12, 24h, then daily until oral intake tolerated [8]
• Uncomplicated P. falciparum: Artemether-lumefantrine 4 tabs BID x 3 days OR Atovaquone-proguanil 4 tabs daily x 3 days
• P. vivax/ovale (chloroquine-sensitive): Chloroquine phosphate PLUS Primaquine 30mg daily x 14 days (after G6PD testing) [9]
• P. vivax/ovale (chloroquine-resistant): ACT PLUS Primaquine for radical cure
• P. malariae: Chloroquine alone (no hypnozoite stage)
• P. knowlesi: Treat as P. falciparum (ACT or IV artesunate if severe) [10]
• Supportive care: Hourly glucose monitoring (first 24h), judicious fluid resuscitation, blood transfusion if Hb less than 7 g/dL
• Exchange transfusion: Consider if parasitemia > 10% with severe disease or > 5% with non-response to therapy

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Overview

Malaria is a life-threatening parasitic disease caused by Plasmodium species transmitted through the bite of infected female Anopheles mosquitoes. Despite being preventable and curable, malaria remains one of the world's most significant infectious diseases, with an estimated 249 million cases and 608,000 deaths globally in 2022, predominantly affecting sub-Saharan Africa [1].

Five Plasmodium species cause human malaria: P. falciparum (most severe), P. vivax (most widespread), P. ovale (two subspecies: P. o. curtisi and P. o. wallikeri), P. malariae, and P. knowlesi (zoonotic from macaque monkeys). P. falciparum accounts for the vast majority of malaria-related deaths due to its unique pathophysiology involving cytoadherence and sequestration in vital organs [2].

In non-endemic countries, malaria is primarily a disease of returning travellers. The UK reports approximately 1,300-1,800 imported cases annually, with similar numbers in the United States. Delay in diagnosis and treatment is the primary cause of mortality in travellers, with case fatality rates of 0.5-1.0% in non-immune individuals - significantly higher than in endemic populations with partial immunity [11].

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Epidemiology

Global Burden

Geographic Distribution by Species

Risk Factors for Severe Disease

Host Factors:

• Non-immune status (travelers from non-endemic areas)
• Age extremes (children less than 5 years, elderly > 65 years)
• Pregnancy (especially primigravidae and second trimester)
• Asplenia or hyposplenia
• Immunosuppression (HIV/AIDS, chemotherapy, biologics)
• Genetic factors: Absence of protective traits (sickle cell trait, G6PD deficiency, α-thalassemia provide partial protection)

Parasite Factors:

• P. falciparum infection (vs. other species)
• High parasite burden (> 2% parasitemia)
• Artemisinin resistance (emerging in SE Asia) [12]

Healthcare Access:

• Delay in diagnosis (> 72 hours after symptom onset)
• Inappropriate empiric antimicrobial therapy
• Lack of ICU facilities

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Aetiology & Pathophysiology

Transmission

Vector Biology:

• Female Anopheles mosquitoes (> 400 species, ~30 efficient vectors)
• Nocturnal feeding behavior (dusk to dawn)
• Peak biting times: 22:00-03:00
• Flight range: Typically less than 2 km from breeding sites
• Aquatic larvae in stagnant water

Incubation Periods:

Alternative Transmission Routes:

• Blood transfusion (rare; 1-2 cases/year in developed countries)
• Organ transplantation
• Congenital transmission (placental or perinatal)
• Needlestick injury in healthcare workers
• "Airport malaria" (mosquitoes transported in aircraft)

Parasite Life Cycle

Sporogonic Cycle (in Mosquito):

1. Female Anopheles ingests gametocytes during blood meal
2. Fertilization occurs in mosquito midgut → ookinete
3. Ookinete penetrates gut wall → oocyst
4. Oocyst ruptures releasing sporozoites (10-14 days)
5. Sporozoites migrate to salivary glands (infectious stage)

Exo-erythrocytic Cycle (Hepatic Stage):

1. Sporozoites injected during mosquito bite (10-100 per bite)
2. Within 30-60 minutes, sporozoites invade hepatocytes
3. Asexual reproduction (schizogony) over 6-15 days
4. Each infected hepatocyte produces 10,000-30,000 merozoites
5. Hypnozoites (P. vivax and P. ovale only): Dormant hepatic forms that can reactivate months to years later, causing relapses

Erythrocytic Cycle (Blood Stage):

1. Merozoites invade erythrocytes via specific receptors:

   • P. vivax: Duffy antigen (DARC) - explains rarity in West Africa where Duffy-negative phenotype predominates
   • P. falciparum: Multiple receptors (glycophorins, CD147, basigin) - can invade all age RBCs
   • P. vivax/ovale: Preferentially invade reticulocytes
   • P. malariae: Preferentially invades mature RBCs

2. Ring stage (trophozoite): 0-24 hours

3. Mature trophozoite: 24-36 hours

4. Schizont: 36-48 hours (72 hours for P. malariae)

5. RBC rupture releases 8-32 merozoites + toxins → clinical symptoms

6. Some merozoites differentiate into gametocytes (sexual stage)

Replication Cycles:

• P. falciparum, vivax, ovale: 48 hours (tertian pattern)
• P. malariae: 72 hours (quartan pattern)
• P. knowlesi: 24 hours (quotidian pattern - daily fever spikes)

P. falciparum-Specific Pathophysiology

Cytoadherence and Sequestration:

P. falciparum-infected RBCs (iRBCs) express variant surface antigens, primarily Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), on the RBC surface. These proteins mediate adherence to:

• Endothelial receptors: ICAM-1, VCAM-1, CD36, EPCR (endothelial protein C receptor)
• Uninfected RBCs (rosetting)
• Placental tissue (CSA - chondroitin sulfate A) in pregnancy

Consequences of Sequestration:

1. Microvascular obstruction: Reduced blood flow to vital organs
2. Tissue hypoxia: Lactic acidosis, organ dysfunction
3. Endothelial activation: Cytokine release (TNF-α, IL-1, IL-6), increased permeability
4. Blood-brain barrier disruption: Cerebral edema, raised ICP (cerebral malaria)
5. Underestimation of disease burden: Mature parasites sequestered in deep tissues are not seen on peripheral blood smears

Rosetting:

• iRBCs bind to uninfected RBCs forming rosettes
• Contributes to microvascular obstruction
• Associated with severe disease phenotype

Hemolysis and Anemia

Mechanisms:

1. Direct parasite-induced lysis: Rupture of infected RBCs every 48-72 hours
2. Immune-mediated destruction: Antibody and complement deposition on both infected and uninfected RBCs
3. Splenic clearance: Enhanced removal of parasitized and damaged RBCs
4. Dyserythropoiesis: Bone marrow suppression by inflammatory cytokines
5. Hemophagocytosis: In severe disease

Blackwater Fever:

• Massive intravascular hemolysis with hemoglobinuria
• Dark "Coca-Cola" colored urine
• Historical association with quinine (rare with modern therapy)
• Mechanism: G6PD deficiency, immune-mediated hemolysis
• Mortality: 20-30% if untreated

Metabolic Derangements

Hypoglycemia:

• Prevalence: 8-15% in severe malaria, up to 50% in pregnant women [13]
• Mechanisms:
  1. Increased glucose consumption by parasites (up to 70× normal)
  2. Impaired hepatic gluconeogenesis
  3. Quinine/quinidine-induced hyperinsulinemia (stimulates pancreatic β-cells)
  4. Depletion of glycogen stores
  5. Increased insulin sensitivity in severe disease
• Recurrent hypoglycemia is common - requires hourly glucose monitoring
• Associated with increased mortality and neurological sequelae

Lactic Acidosis:

• Single best predictor of mortality in severe malaria [7]
• Lactate > 5 mmol/L: 75% mortality; lactate > 10 mmol/L: > 90% mortality
• Mechanisms:
  1. Anaerobic glycolysis due to microvascular obstruction
  2. Impaired hepatic lactate clearance
  3. Increased glycolysis by parasites
• Acidosis (base deficit > 8 mEq/L or pH less than 7.25) defines severe malaria

Other Metabolic Abnormalities:

• Hyponatremia (dilutional, SIADH-like syndrome)
• Hypophosphatemia (refeeding syndrome with treatment)
• Elevated uric acid (nucleotide breakdown)

Immunopathology

Acute Phase Response:

• Massive cytokine release: TNF-α, IL-1β, IL-6, IL-8, IFN-γ
• Systemic inflammatory response syndrome (SIRS)
• Contributes to fever, rigors, and end-organ damage

Protective vs. Pathogenic Immunity:

• Antibody responses develop slowly (years of exposure)
• Cell-mediated immunity critical for hepatic stage clearance
• Excessive inflammation contributes to severe disease
• Partial immunity in endemic populations reduces mortality but not infection

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Clinical Presentation

Classic Malaria Paroxysm

Three-Stage Fever Pattern (classic but present in less than 50% of cases):

1. Cold Stage (15-60 minutes):

   • Intense chills and rigors
   • Teeth chattering
   • Piloerection ("goose bumps")
   • Patient feels cold despite normal/elevated temperature
   • Peripheral vasoconstriction

2. Hot Stage (2-6 hours):

   • High fever: 39-41°C (102-106°F)
   • Facial flushing
   • Severe headache (frontal, retro-orbital)
   • Nausea, vomiting
   • Tachycardia, tachypnea
   • Confusion in severe cases

3. Sweating Stage (2-4 hours):

   • Profuse diaphoresis
   • Defervescence
   • Marked fatigue and weakness
   • Patient often falls asleep

Periodicity:

• P. falciparum: Often irregular, especially early (continuous fever common)
• P. vivax/ovale: 48-hour cycles (tertian fever - every other day)
• P. malariae: 72-hour cycles (quartan fever - every third day)
• P. knowlesi: 24-hour cycles (quotidian fever - daily)

Common Symptoms (Uncomplicated Malaria)

Absence of Specific Symptoms:

• Malaria presents non-specifically
• No pathognomonic clinical features
• High index of suspicion essential in anyone with fever + travel history

Physical Examination Findings

Splenic Rupture:

• Incidence: 0.1-2% of acute malaria
• More common with P. vivax than P. falciparum
• Presentation: Acute abdominal pain, left shoulder pain (Kehr's sign), shock
• Usually occurs 4-8 weeks after initial infection
• Management: Emergency splenectomy, blood transfusion

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Severe Malaria

WHO 2023 Criteria for Severe Malaria [8]

Any one or more of the following in the presence of P. falciparum parasitemia (or mixed infection including P. falciparum or P. knowlesi):

Additional Severity Markers (Not in WHO Criteria but Important):

• Parasitemia 2-10% with any clinical/laboratory abnormality
• Age > 60 years with any complication
• Pregnancy with any complication
• Hyperbilirubinemia (> 50 μmol/L) + parasitemia > 100,000/μL
• Schizont forms on peripheral smear (indicates sequestration)

Cerebral Malaria

Definition:

• Unarousable coma (GCS ≤11, unable to localize pain) persisting > 30 minutes after termination of seizure
• In presence of P. falciparum parasitemia
• With no other identifiable cause of encephalopathy

Clinical Features:

• Diffuse, symmetric encephalopathy (not focal)
• Seizures in 50-80% (generalized tonic-clonic)
• Abnormal posturing: Decorticate (flexor) or decerebrate (extensor)
• Absent doll's eye reflex
• Brainstem signs in severe cases
• Retinal changes (in 15-30%): Hemorrhages, papilledema, vessel discoloration, whitening

Ophthalmoscopy in Cerebral Malaria:

• Retinal whitening (most specific finding)
• Retinal hemorrhages
• Vessel changes (orange/white discoloration)
• Papilledema
• Presence strongly supports diagnosis of cerebral malaria vs. other causes of coma

Differential Diagnosis:

• Bacterial meningitis (CSF usually normal in cerebral malaria)
• Viral encephalitis (HSV, JE, arbovirus)
• Metabolic encephalopathy (hypoglycemia, uremia, hepatic)
• Septic encephalopathy
• Stroke (focal signs unusual in malaria)

Investigations:

• CSF analysis: Opening pressure often elevated (> 20 cm H₂O); protein mildly elevated (less than 100 mg/dL); glucose normal; WBC less than 50/μL (typically lymphocytic); lactate may be elevated
• CT/MRI brain: Usually normal or shows diffuse cerebral edema; excludes other pathology
• EEG: Diffuse slowing; no specific pattern

Prognosis:

• Mortality: 15-25% even with optimal treatment [2]
• Neurological sequelae in survivors: 10-15% overall, 25% in children
• Sequelae include: Cognitive impairment, behavioral changes, epilepsy, hemiparesis, ataxia, cortical blindness
• Most recovery occurs within 6 months; residual deficits beyond 12 months are usually permanent

Severe Malarial Anemia

Pathophysiology:

• Rapid hemolysis (up to 10% Hb drop in 24 hours)
• Bone marrow suppression
• Splenic sequestration
• Acute on chronic anemia in endemic populations

Clinical Features:

• Severe pallor (conjunctiva, palms)
• Tachycardia, dyspnea
• High-output cardiac failure in severe cases
• Jaundice (hemolytic pattern)

Management:

• Transfuse if Hb less than 7 g/dL (adults) or less than 5 g/dL (children) OR symptomatic
• Use packed RBCs (not whole blood)
• Furosemide 1 mg/kg with each unit if risk of volume overload
• Monitor for transfusion reactions and TRALI

Acute Kidney Injury (AKI)

Incidence: 10-40% of severe malaria in adults; less common in children (5-10%)

Pathophysiology:

• Acute tubular necrosis (ATN) from:
  1. Sequestration and microvascular obstruction
  2. Hemoglobinuria (hemolysis)
  3. Volume depletion
  4. Sepsis/inflammatory mediators
• Usually reversible with treatment

Clinical Features:

• Oliguria (less than 400 mL/24h) or anuria
• Elevated creatinine and urea
• Hyperkalemia, metabolic acidosis
• Volume overload (if over-resuscitated)

Management:

• Conservative fluid management (avoid fluid overload)
• Monitor electrolytes closely (K⁺, PO₄³⁻)
• Early renal replacement therapy if:
  • Refractory hyperkalemia (K⁺ > 6.5 mmol/L)
  • Severe acidosis (pH less than 7.1)
  • Volume overload with pulmonary edema
  • Uremia with encephalopathy
  • Anuria > 24 hours
• Continuous RRT preferred in hemodynamically unstable patients
• Prognosis: Usually complete recovery if patient survives

Pulmonary Edema and ARDS

Incidence: 2-10% of severe malaria; higher in adults, pregnancy, over-resuscitation [14]

Pathophysiology:

• Increased pulmonary capillary permeability (ARDS mechanism)
• Fluid overload (iatrogenic)
• Cardiac dysfunction
• Usually develops 24-72 hours after starting treatment (paradoxical)

Clinical Features:

• Dyspnea, tachypnea (RR > 30)
• Hypoxemia (SpO₂ less than 92% on room air)
• Bilateral crackles
• Productive cough with pink frothy sputum
• CXR: Bilateral infiltrates, normal heart size

Management:

• Oxygen therapy to maintain SpO₂ > 92%
• Mechanical ventilation with ARDS protocol:
  • Low tidal volume (6 mL/kg ideal body weight)
  • PEEP titrated to FiO₂ requirement
  • Plateau pressure less than 30 cm H₂O
  • Prone positioning if severe
• Conservative fluid strategy (negative balance)
• Furosemide for diuresis
• Mortality: 40-80% once established

Metabolic Acidosis

Definition: pH less than 7.35 or base deficit > 8 mEq/L or lactate > 5 mmol/L

Strongest predictor of mortality in severe malaria [7]

Pathophysiology:

• Lactic acidosis from tissue hypoxia (anaerobic metabolism)
• Ketoacidosis (starvation)
• Renal tubular acidosis
• Impaired hepatic lactate clearance

Management:

• Treat underlying cause (antimalarials, resuscitation)
• Avoid bicarbonate (does not improve outcomes, may worsen intracellular acidosis)
• Mechanical ventilation if respiratory compensation inadequate
• Consider RRT if severe and refractory

Hypoglycemia

Definition: Blood glucose less than 2.2 mmol/L (less than 40 mg/dL)

Incidence: 8-15% severe malaria adults; up to 50% in pregnant women [13]

Risk Factors:

• Quinine/quinidine therapy
• Pregnancy
• Prolonged fasting
• High parasite burden
• Young children

Clinical Features:

• Often asymptomatic (masked by coma)
• Sweating, tachycardia
• Altered consciousness, seizures
• Can mimic or worsen cerebral malaria

Management:

• Treatment:
  • "Conscious: Oral glucose 50g"
  • "Unconscious: IV 50% dextrose 50 mL (adults) or 2-5 mL/kg (children)"
  • Follow with D5 or D10 infusion
• Prevention:
  • Monitor glucose hourly for first 24 hours
  • Then every 4-6 hours until stable
  • Maintain glucose 5-10 mmol/L
  • Early enteral feeding when tolerated

Shock (Algid Malaria)

Definition: SBP less than 80 mmHg in adults with signs of impaired tissue perfusion

Pathophysiology:

• Hypovolemia (poor oral intake, vomiting, insensible losses)
• Capillary leak syndrome (cytokine-mediated)
• Myocardial dysfunction
• Concomitant bacterial sepsis (10-30% of severe malaria) [15]

Management:

• Fluid resuscitation: Cautious boluses (10 mL/kg over 30-60 min)
• Avoid excessive fluids (risk of pulmonary edema)
• Blood cultures before antibiotics
• Broad-spectrum antibiotics if sepsis suspected
• Vasopressors (norepinephrine first-line) if fluid-refractory
• Consider adrenal insufficiency (hydrocortisone if refractory shock)

Disseminated Intravascular Coagulation (DIC)

Incidence: 5-10% of severe malaria

Laboratory Features:

• Thrombocytopenia (less than 50,000/μL)
• Prolonged PT/aPTT
• Low fibrinogen (less than 150 mg/dL)
• Elevated D-dimer
• Schistocytes on blood film

Management:

• Treat underlying malaria
• Platelet transfusion if bleeding + platelets less than 20,000/μL
• FFP if bleeding + INR > 2.0
• Cryoprecipitate if fibrinogen less than 100 mg/dL
• Avoid heparin (no benefit, risk of bleeding)

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Differential Diagnosis

Febrile Illness in Returning Traveller

"Cannot Miss" Diagnoses:

Common Travel-Related Infections:

Co-infections in Malaria

Bacterial Co-infections:

• Incidence: 5-30% in severe malaria, especially children [15]
• Organisms: Non-typhoidal Salmonella, S. pneumoniae, E. coli, Staphylococcus aureus
• Always consider in shock or ARDS
• Blood cultures indicated in all severe malaria

Viral Co-infections:

• HIV: Increases risk of severe malaria, treatment failure
• Hepatitis B/C: Common in endemic areas
• EBV: Can cause similar symptoms

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Diagnostic Approach

Clinical Suspicion

Malaria should be suspected in ANY patient with:

1. Fever (or history of fever)
2. Travel to malaria-endemic area
3. Within 12 months of return (up to 3 years for P. vivax/ovale)

Even if:

• Took chemoprophylaxis (not 100% effective)
• No mosquito bites recalled
• Brief travel or airport transit only
• Vaccinations up to date (no malaria vaccine in routine use)

Laboratory Diagnosis

Blood Film Microscopy (Gold Standard) [5]

Thick Blood Film:

• Purpose: Detection (screening test)
• Sensitivity: > 95% at > 100 parasites/μL; 50-75% at less than 100 parasites/μL
• Technique: RBCs lysed to concentrate parasites; 100 high-power fields examined
• Advantages: More sensitive than thin film; rapid screening
• Disadvantages: Species identification difficult; cannot quantify parasitemia accurately

Thin Blood Film:

• Purpose: Species identification and parasitemia quantification
• Sensitivity: Lower than thick film (detects > 500 parasites/μL reliably)
• Technique: RBC morphology preserved; count parasites per 1000 RBCs
• Advantages: Definitive species identification; accurate parasitemia
• Parasitemia calculation: (Number of infected RBCs / 1000 RBCs) × 100%

Microscopic Species Identification:

Parasitemia Quantification:

• Method 1: Count parasites per 1000 RBCs; divide by 10 to get percentage
• Method 2: Count parasites per 200 WBCs; multiply by WBC count and divide by RBC count
• Interpretation:
  • "Light: less than 1% (less than 50,000/μL)"
  • "Moderate: 1-4% (50,000-200,000/μL)"
  • "Heavy: > 5% (> 250,000/μL) - severe disease threshold"
  • "Critical: > 10% (> 500,000/μL) - consider exchange transfusion"

Repeat Testing:

• Parasites may not be detectable in early infection
• If initial smear negative but high suspicion: Repeat at 12-24 hour intervals
• Test 3 times over 72 hours before excluding malaria
• Parasitemia fluctuates with RBC rupture cycles

Rapid Diagnostic Tests (RDTs) [6]

Technology:

• Lateral flow immunochromatographic assays
• Detect parasite antigens in whole blood
• Results in 10-20 minutes

Antigen Targets:

Performance:

• Sensitivity: 95-99% for P. falciparum at > 100 parasites/μL [6]
• Specificity: 95-98%
• Advantages: Rapid, no microscopy expertise needed, point-of-care
• Limitations:
  • Lower sensitivity at low parasitemia (less than 100/μL)
  • Cannot quantify parasitemia
  • HRP2 persists weeks after treatment (not useful for monitoring cure)
  • HRP2 deletions in some P. falciparum strains (5-10% in Horn of Africa)
  • Does not detect all species equally well

Clinical Use:

• Initial screening in resource-limited settings
• Supplement (not replacement) for microscopy
• Negative RDT does not exclude malaria in low parasitemia
• Always confirm with microscopy when available

Molecular Diagnostics

PCR (Polymerase Chain Reaction):

• Highest sensitivity (detects 1-5 parasites/μL)
• Definitive species identification (including mixed infections)
• Detects artemisinin resistance mutations (kelch13)
• Not widely available for acute diagnosis (slow turnaround)
• Research and reference laboratory use

Loop-mediated Isothermal Amplification (LAMP):

• Point-of-care molecular test
• High sensitivity and specificity
• Faster than PCR (30-60 minutes)
• Emerging technology

Additional Laboratory Studies

Baseline Investigations for All Malaria Cases:

Thrombocytopenia in Malaria:

• Present in 60-90% of cases
• Severity correlates with disease severity
• Mechanism: Splenic sequestration, immune destruction, DIC
• Platelet count > 20,000/μL rarely causes bleeding
• Sensitive but non-specific finding

Anemia Patterns:

• Normocytic or macrocytic (reticulocytosis)
• Elevated LDH, indirect bilirubin (hemolysis)
• Low haptoglobin
• Reticulocyte count may be low initially (bone marrow suppression)

Imaging

Indications:

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Classification and Staging

Disease Severity Classification

Uncomplicated Malaria:

• Presence of parasitemia with symptoms
• No WHO criteria for severe malaria
• Parasitemia typically less than 2%
• Can be managed outpatient in select cases (non-falciparum, reliable patient)

Moderately Severe Malaria:

• Parasitemia 2-5% OR
• Any single laboratory abnormality (thrombocytopenia, anemia, renal impairment) without WHO severe criteria
• Requires inpatient monitoring
• Risk of progression to severe malaria

Severe Malaria:

• Any WHO criteria for severe malaria (see above)
• Requires ICU-level care
• Parenteral antimalarial therapy (IV artesunate)
• Mortality risk: 10-40% depending on criteria

Prognostic Scoring

Indicators of Poor Prognosis:

1. Lactate > 5 mmol/L (strongest predictor) [7]
2. Base deficit > 8 mEq/L
3. Hyperparasitemia > 10%
4. Coma (GCS ≤8)
5. Shock requiring vasopressors
6. Acute kidney injury requiring RRT
7. ARDS
8. Age > 60 years or less than 2 years
9. Pregnancy
10. Schizont forms on peripheral smear (indicates deep tissue sequestration)

Mortality Prediction:

• 0-1 risk factors: less than 5% mortality
• 2-3 risk factors: 10-25% mortality
• ≥4 risk factors: > 40% mortality

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Management

Severe Malaria Treatment [8]

First-Line: Intravenous Artesunate

DOSING REGIMEN:
- Loading: 2.4 mg/kg IV at 0, 12, and 24 hours
- Maintenance: 2.4 mg/kg IV once daily
- Duration: Until patient can tolerate oral medication (usually 24-72h)
- Follow-on: Complete course with oral ACT (artemether-lumefantrine or other)

ADMINISTRATION:
- Reconstitute with 1 mL 5% sodium bicarbonate
- Dilute in 5-10 mL 5% dextrose or 0.9% saline
- Administer IV bolus over 1-2 minutes
- Stable for 1 hour after reconstitution

MONITORING:
- Parasitemia every 12-24 hours until less than 1%
- Glucose hourly for first 24h, then every 4-6h
- Vital signs every 1-2 hours
- FBC, renal function, lactate daily
- ECG (QTc monitoring)

Evidence Base:

• SEAQUAMAT trial (2005): Artesunate reduced mortality by 35% vs. quinine in Asian adults [3]
• AQUAMAT trial (2010): Artesunate reduced mortality by 23% vs. quinine in African children [4]
• Number needed to treat: 13-15 patients to prevent 1 death
• Faster parasite clearance: 2.5× faster than quinine
• Superior in all subgroups analyzed

Alternative: Intravenous Quinidine (if artesunate unavailable)

DOSING REGIMEN:
- Loading dose: 10 mg/kg quinidine base IV over 1-2 hours*
- Maintenance: 0.02 mg/kg/min continuous infusion
- Maximum loading: 600 mg base
- Duration: Until parasitemia less than 1% and oral intake tolerated
- Switch to: Oral quinine 650 mg TID + doxycycline 100 mg BID

*Omit loading dose if patient received quinine/mefloquine in prior 24h

ADMINISTRATION:
- Dilute in 10 mL/kg 0.9% saline or 5% dextrose
- Use infusion pump for continuous infusion
- Administer through central or large peripheral IV

MONITORING:
- Continuous cardiac monitoring (telemetry mandatory)
- QTc interval (baseline, 2h, 6h, then daily)
- Stop if QTc > 600 ms or increases > 25% from baseline
- Blood pressure every 15 min during loading, then hourly
- Glucose every 1-2 hours (quinidine stimulates insulin release)
- Quinidine levels if available (target 3-8 mg/L)

ADVERSE EFFECTS:
- Hypoglycemia (20-50% of patients)
- QTc prolongation (torsades de pointes risk)
- Hypotension (reduce infusion rate)
- Cinchonism: Tinnitus, hearing loss, vertigo, visual disturbance

Artesunate vs. Quinidine:

• Artesunate is superior in all aspects (efficacy, safety, ease of use)
• Quinidine requires intensive monitoring
• Artesunate should be available in all centers managing severe malaria
• CDC Malaria Hotline (770-488-7788) can provide emergency artesunate in US

Adjunctive Management of Severe Malaria

Hypoglycemia Management:

TREATMENT:
- Conscious: 50g oral glucose
- Unconscious: 50 mL IV 50% dextrose (adults); 2-5 mL/kg (children)
- Maintenance: D5 or D10 infusion at 100-150 mL/h

MONITORING:
- Hourly glucose for first 24h
- Every 4-6h subsequently
- Target glucose: 5-10 mmol/L (90-180 mg/dL)
- Recurrent hypoglycemia common (check before assuming cerebral malaria worsening)

Fluid Management:

PRINCIPLES:
- Conservative approach (avoid fluid overload → pulmonary edema)
- Most patients are euvolemic or mildly dehydrated
- Aggressive resuscitation associated with worse outcomes [14]

APPROACH:
- Assess volume status carefully (JVP, lung sounds, skin turgor, urine output)
- If hypovolemic: 10 mL/kg crystalloid bolus over 30-60 min
- Reassess after each bolus
- Maintenance: 1-1.5 mL/kg/h
- If shock: Vasopressors early rather than large volume
- Furosemide if evidence of fluid overload

Blood Transfusion:

INDICATIONS:
- Hb less than 7 g/dL (adults) with symptoms
- Hb less than 5 g/dL (children) regardless of symptoms
- Hb less than 10 g/dL with severe acidosis or shock

PRODUCT:
- Packed RBCs (not whole blood)
- Cross-match and screen
- CMV-negative if available

ADMINISTRATION:
- 1 unit over 2-4 hours (slower if risk of volume overload)
- Furosemide 10-20 mg IV before each unit if cardiac/renal disease
- Monitor for transfusion reactions

Seizure Management:

FIRST-LINE:
- Lorazepam 0.1 mg/kg IV (max 4 mg) OR
- Diazepam 0.15-0.2 mg/kg IV (max 10 mg)

SECOND-LINE (status epilepticus):
- Phenytoin 20 mg/kg IV loading over 30 min (max 1g) OR
- Levetiracetam 60 mg/kg IV (max 4.5g)

PROPHYLAXIS:
- Not recommended (no benefit, may mask worsening)
- Treat seizures as they occur

Renal Replacement Therapy:

INDICATIONS:
- Anuria > 24 hours
- Refractory hyperkalemia (K⁺ > 6.5 mmol/L)
- Severe acidosis (pH less than 7.1) unresponsive to treatment
- Volume overload with pulmonary edema
- Uremia (BUN > 100 mg/dL with encephalopathy)

MODALITY:
- Continuous RRT (CRRT) preferred in hemodynamically unstable
- Intermittent hemodialysis if stable
- Avoid peritoneal dialysis (high infection risk, less efficient)

Mechanical Ventilation:

INDICATIONS:
- ARDS (PaO₂/FiO₂ less than 200)
- Refractory hypoxemia (SpO₂ less than 90% on high-flow O₂)
- Respiratory failure (apnea, respiratory acidosis)
- Airway protection (GCS less than 8)

STRATEGY (ARDS):
- Low tidal volume: 6 mL/kg ideal body weight
- PEEP: Titrated to FiO₂ (typically 10-15 cm H₂O)
- Plateau pressure less than 30 cm H₂O
- Target SpO₂ 88-95% (avoid hyperoxia)
- Prone positioning if severe (PaO₂/FiO₂ less than 150)
- Conservative fluid strategy

Exchange Transfusion:

Indications:

• Parasitemia > 10% with any severe malaria criterion OR
• Parasitemia > 5% with deterioration despite IV artesunate OR
• Rapidly rising parasitemia

Rationale:

• Removes parasitized RBCs and toxins
• Reduces parasite burden more rapidly than antimalarials alone
• No randomized trials demonstrating benefit, but observational data suggest improved outcomes in hyperparasitemia [16]

Procedure:

• Manual exchange: Remove 500 mL blood, replace with 500 mL pRBCs; repeat 5-7 times
• Automated apheresis: 1-2 blood volumes
• Goal: Reduce parasitemia to less than 1%
• Continue IV artesunate throughout

Complications:

• Volume overload
• Electrolyte imbalances (hypocalcemia, hypokalemia)
• Transfusion reactions
• Line-related complications

Uncomplicated P. falciparum Malaria

First-Line: Artemisinin-Based Combination Therapy (ACT)

All ACTs have > 95% efficacy when taken correctly [17]

Administration Details:

Artemether-lumefantrine (AL):

ADULT DOSE: 4 tablets (80mg artemether + 480mg lumefantrine) at 0, 8, 24, 36, 48, 60 hours
MUST take with fatty food (increases lumefantrine absorption 2-3×):
- Milk (full-fat)
- Peanut butter sandwich
- Ensure/Boost supplement
If vomiting less than 30 min after dose: Repeat dose
If vomiting 30-60 min after dose: Take half dose

Atovaquone-proguanil:

ADULT DOSE: 4 tablets (250mg atovaquone + 100mg proguanil) once daily × 3 days
Take with food (preferably fatty)
Highly effective but expensive
Safe in pregnancy (limited data but appears safe)
Avoid in severe renal impairment (CrCl less than 30 mL/min)

Alternative Regimens (if ACT not available or contraindicated):

Quinine + Doxycycline:

Quinine sulfate 650 mg (10 mg/kg) PO TID × 7 days
PLUS
Doxycycline 100 mg PO BID × 7 days

ADVERSE EFFECTS:
- Cinchonism: Tinnitus (30-50%), nausea (20-30%), vertigo (10-20%)
- Usually mild and resolve after completion
- Hypoglycemia risk

CONTRAINDICATIONS to doxycycline:
- Pregnancy
- Children less than 8 years
- Substitute clindamycin 10 mg/kg TID × 7 days

Monitoring and Follow-up:

• Assess clinical response at 48-72 hours (defervescence expected)
• Repeat blood film at Day 3 (parasitemia should be less than 25% of baseline)
• Repeat blood film at Day 7 (should be negative)
• Day 28 follow-up (exclude late treatment failure)

Treatment Failure:

• Persistent parasitemia or symptoms after 3 days of ACT
• Recurrent parasitemia within 28 days
• Causes: Poor adherence, vomiting, drug resistance, incorrect diagnosis
• Management: Exclude vomiting/malabsorption; use different ACT; consider resistance

P. vivax and P. ovale Treatment

Two-Component Strategy:

1. Schizonticidal therapy: Kills blood-stage parasites
2. Hypnozoiticidal therapy: Eradicates dormant liver stages (prevents relapse)

Chloroquine-Sensitive Areas (Most of Central America, Middle East):

PHASE 1 - CHLOROQUINE (Schizonticidal):
Day 1: Chloroquine phosphate 1000 mg (600 mg base) PO
Day 1 (6h later): 500 mg (300 mg base) PO
Day 2: 500 mg (300 mg base) PO
Day 3: 500 mg (300 mg base) PO
Total dose: 2500 mg (1500 mg base)

PHASE 2 - PRIMAQUINE (Hypnozoiticidal):
Standard dose: 30 mg base (52.6 mg salt) PO daily × 14 days
Alternative: 15 mg base daily × 14 days (if G6PD deficiency concern)
Weekly: 45 mg base once weekly × 8 weeks (for severe G6PD deficiency)

CRITICAL: Check G6PD enzyme level BEFORE primaquine

G6PD Testing and Primaquine Use:

G6PD Deficiency Prevalence:

• Mediterranean: 5-30%
• Sub-Saharan Africa: 10-25%
• Middle East: 5-25%
• Southeast Asia: 5-15%
• Papua New Guinea: 10-30%

G6PD Testing:

• Quantitative enzyme assay (gold standard)
• Qualitative fluorescent spot test (rapid)
• False negatives possible in acute hemolysis (young RBCs have higher G6PD)
• Retest after recovery if initially tested during acute illness

Primaquine Dosing Based on G6PD Status:

Primaquine Contraindications:

• Pregnancy (defer until after delivery and breastfeeding)
• Breastfeeding infant with unknown G6PD status
• Severe G6PD deficiency without ability to monitor
• Methemoglobinemia
• Recent methylene blue exposure

Primaquine Adverse Effects:

• Hemolysis in G6PD deficiency (dose-dependent)
• Methemoglobinemia (mild, less than 10%)
• GI upset (20-30%): Take with food
• Leukopenia (rare)

Alternative: Tafenoquine (Single-Dose Hypnozoiticide):

Dose: 300 mg single dose (taken with chloroquine on Day 1 or 2)
Advantages: Single dose (vs. 14 days primaquine); improved adherence
Disadvantages: Requires quantitative G6PD testing (> 70% activity); longer half-life (14 days) - extended hemolysis risk
FDA approved 2018; not widely available yet

Chloroquine-Resistant Areas (Papua New Guinea, Indonesia):

Use ACT (artemether-lumefantrine or dihydroartemisinin-piperaquine)
PLUS
Primaquine 30 mg base daily × 14 days (after G6PD testing)

ACT dosing same as for P. falciparum

Prevention of Relapses:

• Without primaquine: 30-80% relapse rate over 3 years (P. vivax)
• With primaquine: less than 5% relapse rate
• P. ovale: Lower relapse rate (15-30%), longer latency (up to 4 years)

P. malariae Treatment

No hypnozoite stage → No need for primaquine

Chloroquine-sensitive (worldwide):
- Chloroquine 1500 mg base over 3 days (same regimen as P. vivax)

Chloroquine-resistant (rare):
- ACT (artemether-lumefantrine) × 3 days

Follow-up:
- Can cause chronic low-level parasitemia for years
- Associated with nephrotic syndrome (immune complex glomerulonephritis)
- Monitor renal function if chronic symptoms

P. knowlesi Treatment [10]

"Treat as P. falciparum" - can cause severe disease and death

Uncomplicated:
- ACT (artemether-lumefantrine or artesunate-mefloquine) × 3 days
- Chloroquine + primaquine also effective but ACT preferred

Severe (any WHO criteria):
- IV artesunate (same dosing as P. falciparum)
- Lower threshold for severe disease (24h replication cycle → rapid rise)

Diagnostic pitfall:
- Resembles P. malariae on microscopy (band forms)
- Resembles P. falciparum (multiply infected RBCs)
- PCR or expert microscopy for definitive diagnosis
- High parasitemia (> 20,000/μL) suggests P. knowlesi not P. malariae

Pregnancy and Malaria

Risks of Malaria in Pregnancy:

• Maternal: Severe anemia (2-3× risk), hypoglycemia, pulmonary edema, death
• Fetal: Placental malaria, intrauterine growth restriction, preterm delivery, low birth weight, fetal loss
• Highest risk: Primigravidae, second trimester

Treatment by Trimester:

First Trimester:

UNCOMPLICATED:
Preferred: Quinine 650 mg TID × 7 days + Clindamycin 600 mg TID × 7 days
Alternative: Artemether-lumefantrine (if benefits outweigh risks)

SEVERE:
IV Artesunate (lifesaving; benefits outweigh theoretical teratogenicity risk)
Data from > 4000 exposures show no increased malformation risk [18]

Second and Third Trimester:

UNCOMPLICATED:
First-line: ACT (artemether-lumefantrine or artesunate-mefloquine)
Alternative: Quinine + clindamycin

SEVERE:
IV Artesunate (same as non-pregnant)

AVOID:
- Primaquine (hemolysis in fetus if G6PD deficient; defer until after delivery)
- Doxycycline (teeth staining, bone effects)
- Atovaquone-proguanil (limited safety data)

Monitoring in Pregnancy:

• Lower threshold for admission
• More frequent glucose monitoring (hourly)
• Conservative fluid management (higher ARDS risk)
• Fetal monitoring if viable (> 24 weeks)
• Obstetric consultation
• Consider delivery if deteriorating maternal status at term

Special Populations

Pediatrics:

• Weight-based dosing for all antimalarials
• IV artesunate: 2.4 mg/kg (same as adults)
• Rectal artesunate if IV access difficult (pre-referral treatment)
• Higher risk of hypoglycemia and seizures
• Rapid progression to severe disease

Elderly (> 65 years):

• Higher mortality from severe malaria
• More comorbidities (cardiac, renal)
• Adjust doses for renal/hepatic impairment
• Drug interactions more common
• Conservative fluid management

Asplenia:

• Risk of overwhelming parasitemia
• Lower threshold for parenteral therapy
• Prophylaxis critical for any travel to endemic areas
• Consider exchange transfusion earlier

HIV/AIDS:

• Increased risk of treatment failure
• Higher parasitemia
• More likely to progress to severe disease
• Drug interactions with antiretrovirals
• Cotrimoxazole prophylaxis provides some antimalarial effect

Renal Impairment:

• Avoid atovaquone-proguanil if CrCl less than 30 mL/min
• Reduce quinine dose if severe (> 3 mg/dL creatinine)
• Artemisinin derivatives safe (no dose adjustment)
• Monitor drug levels if available

Hepatic Impairment:

• Avoid atovaquone-proguanil
• Artemisinin derivatives safe
• Monitor quinine levels

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Complications

Early Complications (First 72 Hours):

Late Complications (After 72 Hours):

Post-Artesunate Delayed Hemolysis (PADH):

• Incidence: 10-15% after IV artesunate for severe malaria
• Mechanism: Delayed removal of artesunate-damaged ("pitted") RBCs
• Timing: 7-30 days after treatment
• Features: Asymptomatic Hb drop 1-3 g/dL, hemolysis markers (LDH↑, haptoglobin↓)
• Monitoring: Check Hb at 7, 14, 21, 28 days post-discharge
• Management: Observation; transfusion if symptomatic or Hb less than 7 g/dL

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Prognosis

Uncomplicated Malaria

• With treatment: > 99% cure rate with ACT
• Without treatment:
  • "P. falciparum: High mortality (10-40% in non-immune)"
  • "P. vivax/ovale/malariae: Low mortality but chronic morbidity"

Severe Malaria

Overall Mortality: 10-40% depending on criteria and resource setting

Mortality by Specific Complication:

• Cerebral malaria: 15-25%
• ARDS: 40-80%
• Shock: 40-60%
• Renal failure (requiring RRT): 20-40%
• Severe acidosis (lactate > 10): > 90%
• Multiple organ failure: 60-80%

Prognostic Factors:

Good Prognosis:

• Single organ involvement
• Rapid parasite clearance (less than 24 hours)
• Lactate less than 5 mmol/L
• No acidosis
• Young, previously healthy
• Early treatment with artesunate

Poor Prognosis:

• Lactate > 10 mmol/L
• Deep coma (GCS less than 8)
• ARDS requiring mechanical ventilation
• Age extremes (less than 2 or > 60 years)
• Pregnancy
• Delayed treatment (> 72h from symptom onset)
• Schizont forms on peripheral smear

Long-Term Outcomes

Neurological Sequelae (Cerebral Malaria Survivors):

• Overall: 10-15%
• Children: 25% (higher than adults)
• Types:
  • Cognitive impairment (learning difficulties, memory)
  • Behavioral changes (ADHD-like symptoms)
  • Epilepsy (5-10%)
  • Motor deficits (hemiparesis, ataxia)
  • Cortical blindness
• Recovery: Most improvement in first 6 months; deficits > 12 months usually permanent

Other Long-Term Effects:

• Chronic anemia (months)
• Recurrent malaria (if incomplete treatment)
• Post-malaria neurological syndrome (PMNS): Self-limited tremor, ataxia, psychosis 1-2 months post-treatment
• P. malariae: Nephrotic syndrome (immune complex GN)

---

Prevention

Chemoprophylaxis for Travelers

Indications: All travelers to malaria-endemic areas

Choice Based on Destination:

Prophylaxis Regimens:

Efficacy:

• Atovaquone-proguanil: 96-98%
• Doxycycline: 92-96%
• Mefloquine: 90-95%
• Chloroquine (sensitive areas): 85-95%

Adherence:

• Daily regimens (atovaquone-proguanil, doxycycline): Lower adherence but shorter post-travel duration
• Weekly regimens (mefloquine): Better adherence but longer post-travel duration and more side effects

Personal Protective Measures

"ABCD" of Malaria Prevention:

• Awareness of risk
• Bite prevention
• Chemoprophylaxis
• Diagnosis and treatment (early)

Bite Prevention:

• Insecticide-treated bed nets (ITNs) - most effective
• DEET-containing repellent (20-50% concentration) on exposed skin
• Permethrin-treated clothing
• Long-sleeved shirts and pants (especially dusk to dawn)
• Air conditioning or screened accommodation
• Avoid outdoor activities at peak biting times (22:00-03:00)

Efficacy of Bed Nets:

• Reduce malaria incidence by 50%
• Reduce all-cause child mortality by 20% in endemic areas

Vaccines

RTS,S/AS01 (Mosquirix):

• First malaria vaccine approved (WHO 2021)
• Targets P. falciparum circumsporozoite protein
• Efficacy: 30-50% reduction in clinical malaria over 4 years (4 doses)
• Target: Children in endemic areas (not travelers)
• Administered at 5, 6, 7, and 18 months of age

R21/Matrix-M:

• Second-generation vaccine (WHO recommendation 2023)
• Higher efficacy: 75% in high-transmission settings
• Target: Children in endemic areas
• 3-dose primary series + booster

Not Currently Recommended for Travelers (insufficient efficacy; chemoprophylaxis superior)

---

Disposition

ICU Admission - Mandatory

Any WHO criteria for severe malaria:

• Impaired consciousness (GCS less than 11)
• Respiratory distress or ARDS
• Shock
• Acidosis (pH less than 7.35 or lactate > 5)
• Hypoglycemia (glucose less than 2.2 mmol/L)
• Severe anemia (Hb less than 7 g/dL in adults)
• AKI (creatinine > 3 mg/dL)
• Parasitemia > 5%
• Multiple seizures
• Significant bleeding

ICU-Level Care Includes:

• Continuous monitoring (cardiac, SpO₂, BP)
• IV artesunate administration
• Hourly glucose monitoring (first 24h)
• Mechanical ventilation if needed
• Renal replacement therapy if needed
• Invasive hemodynamic monitoring if shock
• Exchange transfusion capability

Ward Admission

Uncomplicated P. falciparum:

• All cases initially (minimum 24 hours observation)
• Even if parasitemia low and patient well-appearing
• Risk of deterioration in first 48 hours

Moderately Severe Malaria:

• Parasitemia 2-5%
• Single organ dysfunction (e.g., thrombocytopenia, mild anemia)
• Unable to tolerate oral medications
• Vomiting, dehydration

Other Indications:

• Pregnant women (any malaria)
• Children less than 5 years
• Elderly > 65 years
• Significant comorbidities
• Social factors (unreliable follow-up, homeless)

Outpatient Management - Select Cases Only

Safe for Discharge Criteria (ALL must be met):

1. Non-falciparum malaria (P. vivax, ovale, malariae) OR uncomplicated P. falciparum
2. Parasitemia less than 2%
3. No WHO criteria for severe malaria
4. Able to tolerate oral medications
5. No vomiting after observed first dose
6. Reliable patient/family
7. Close follow-up available (48-72h)
8. No high-risk features (pregnancy, extremes of age, comorbidities)
9. Lives within 1 hour of hospital

Discharge Instructions:

• Complete entire course of antimalarials
• Return immediately if: Fever recurs, vomiting, confusion, difficulty breathing, dark urine, yellowing of eyes
• Follow-up at 48-72 hours (clinical assessment)
• Repeat blood film at Day 3, 7, and 28

Follow-Up Schedule

Public Health Reporting

• Malaria is a notifiable disease in most countries
• Report ALL cases to local public health department within 24 hours
• Information to provide:
  • Patient demographics
  • Travel history (countries, dates)
  • Species identified
  • Severity
  • Treatment
  • Prophylaxis use (if any)
• Public health may conduct contact tracing (congenital, transfusion-associated cases)

---

Key Clinical Pearls

Diagnostic Pearls

1. P. falciparum can kill within 48 hours in non-immune individuals - early diagnosis critical
2. Three negative blood films needed to exclude malaria (not one)
3. Thrombocytopenia is the most sensitive finding (80-90% of cases) but non-specific
4. Peripheral parasitemia underestimates disease burden in P. falciparum (sequestration)
5. Schizont forms on peripheral smear indicate heavy sequestration and severe disease
6. RDTs can remain positive for 2-4 weeks after cure (HRP2 antigen persistence)
7. Check for concurrent infections - travelers can have multiple diseases simultaneously
8. Absence of fever does not exclude malaria - patient may have taken antipyretics recently

Treatment Pearls

1. IV artesunate is 35% more effective than quinine - insist on its availability [3,4]
2. Hypoglycemia is recurrent - glucose monitoring must continue beyond initial correction
3. Aggressive fluid resuscitation worsens outcomes - conservative approach [14]
4. Always check G6PD before primaquine - hemolysis can be life-threatening
5. Primaquine is essential for P. vivax/ovale - prevents relapses (30-80% without it)
6. Complete full ACT course after IV artesunate - prevents recrudescence
7. Post-artesunate delayed hemolysis occurs in 10-15% - check Hb weekly × 4 weeks
8. Exchange transfusion for parasitemia > 10% with severe disease
9. Artemether-lumefantrine must be taken with fat - critical for absorption
10. Quinidine requires continuous cardiac monitoring - risk of torsades

Exam/Viva Pearls

1. WHO severe malaria criteria: Memorize all 12 (frequently asked)
2. Artesunate dosing: 2.4 mg/kg at 0, 12, 24h, then daily
3. SEAQUAMAT and AQUAMAT trials: Evidence for artesunate superiority [3,4]
4. Hypnozoites: Only P. vivax and P. ovale; require primaquine for radical cure
5. G6PD deficiency: Check before primaquine; Mediterranean, African, Asian populations
6. Blackwater fever: Massive intravascular hemolysis with dark urine (hemoglobinuria)
7. P. knowlesi: 24-hour cycle; can be severe; treat as falciparum
8. Duffy antigen: Required for P. vivax invasion; explains rarity in West Africa (Duffy-negative)
9. Cytoadherence: PfEMP1 binds ICAM-1, VCAM-1, CD36, EPCR → sequestration
10. Lactate > 5 mmol/L: Strongest predictor of mortality [7]

Common Mistakes (Exam Failures)

❌ Mistake 1: Single negative blood film excludes malaria ✅ Correct: Repeat at 12-24h intervals × 3 before exclusion

❌ Mistake 2: Giving primaquine without G6PD testing ✅ Correct: Always check G6PD first (hemolysis risk)

❌ Mistake 3: Aggressive fluid resuscitation in severe malaria ✅ Correct: Conservative fluids (avoid pulmonary edema)

❌ Mistake 4: Treating P. vivax with ACT only (no primaquine) ✅ Correct: ACT + primaquine for radical cure (prevents relapse)

❌ Mistake 5: Using quinine instead of artesunate for severe malaria ✅ Correct: Artesunate is superior (35% mortality reduction)

❌ Mistake 6: Discharging uncomplicated P. falciparum same day ✅ Correct: Minimum 24h observation (risk of deterioration)

❌ Mistake 7: Forgetting to complete oral ACT after IV artesunate ✅ Correct: 3-day oral ACT essential for cure

❌ Mistake 8: Missing concurrent bacterial sepsis in severe malaria ✅ Correct: Blood cultures and empiric antibiotics if shock/ARDS [15]

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Viva/OSCE Scenarios

Scenario 1: Severe Malaria

Examiner: "A 35-year-old businessman presents with 3 days of fever after returning from Nigeria 1 week ago. He is confused with GCS 10. What is your approach?"

Model Answer: "This is a medical emergency. My differential includes severe falciparum malaria, bacterial meningitis, and viral encephalitis. Given recent travel to a malaria-endemic area, severe malaria is most likely.

I would immediately:

1. Resuscitation: Assess airway, breathing, circulation; high-flow oxygen; IV access
2. Urgent investigations: Thick and thin blood films, RDT, glucose (point-of-care), FBC, BMP, lactate, ABG, blood cultures
3. Empiric treatment: Start IV artesunate 2.4 mg/kg immediately (don't wait for films if severe)
4. ICU admission: Continuous monitoring, hourly glucose, manage complications

For severe malaria specifically:

• Check for WHO severity criteria: Impaired consciousness (GCS 10), parasitemia level, acidosis, hypoglycemia, renal function, hemoglobin
• Artesunate 2.4 mg/kg IV at 0, 12, 24h, then daily until oral intake tolerated
• Monitor glucose hourly (hypoglycemia common and recurrent)
• Conservative fluid management (avoid pulmonary edema)
• Consider co-infection (blood cultures, empiric antibiotics if shocked)
• Follow parasitemia to less than 1% then switch to oral ACT for 3 days
• Infectious disease consult

The evidence for IV artesunate comes from SEAQUAMAT and AQUAMAT trials showing 35% mortality reduction versus quinine."

Scenario 2: P. vivax Treatment

Examiner: "A 28-year-old woman has uncomplicated P. vivax malaria. How would you treat her?"

Model Answer: "P. vivax requires two-phase treatment:

Phase 1 - Blood stage (schizonticidal):

• If from chloroquine-sensitive area (Central America, Middle East): Chloroquine 1500 mg base over 3 days
• If from resistant area (Papua New Guinea, Indonesia): ACT such as artemether-lumefantrine

Phase 2 - Liver stage (hypnozoiticidal):

• Primaquine 30 mg base daily for 14 days
• CRITICAL: Check G6PD enzyme level BEFORE starting primaquine
• If G6PD deficient: Weekly primaquine 45 mg × 8 weeks OR defer if pregnant

Why primaquine is essential:

• P. vivax forms dormant hypnozoites in liver
• Without primaquine: 30-80% relapse rate
• With primaquine: less than 5% relapse rate

Contraindications to primaquine:

• Pregnancy (defer until after delivery and breastfeeding)
• G6PD deficiency (causes hemolysis - can be life-threatening)
• Unknown G6PD status in at-risk populations

Follow-up:

• Clinical response at 48-72 hours
• Blood film Day 7 (should be negative)
• Monitor for relapses over 3 years (late presentations possible)"

Scenario 3: Pregnant Woman with Malaria

Examiner: "A pregnant woman at 10 weeks gestation has P. falciparum malaria. What are your concerns and how would you manage her?"

Model Answer: "Pregnancy increases risk of severe malaria and complications:

Maternal risks:

• Severe anemia (2-3× risk)
• Hypoglycemia (up to 50%)
• Pulmonary edema
• Higher mortality

Fetal risks:

• Placental malaria
• IUGR, preterm delivery
• Low birth weight
• Fetal loss

Management approach:

If uncomplicated (no severe criteria):

• First trimester: Quinine 650 mg TID + clindamycin 600 mg TID for 7 days
  • Artemisinin derivatives avoided if possible (limited first-trimester data, though > 4000 exposures show no increased malformations)
• Second/third trimester: ACT (artemether-lumefantrine) is first-line

If severe:

• IV artesunate regardless of trimester (lifesaving; benefits outweigh risks)
• Evidence from > 4000 exposures shows no teratogenicity

Additional management:

• Lower threshold for admission
• Hourly glucose monitoring (higher hypoglycemia risk)
• Conservative fluids (higher ARDS risk)
• Fetal monitoring if viable (> 24 weeks)
• Obstetric consultation
• Avoid primaquine (defer until after delivery and breastfeeding)
• Iron and folate supplementation

Delivery considerations:

• May need early delivery if maternal deterioration
• Examine placenta for placental malaria"

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References

1. World Health Organization. World Malaria Report 2023. Geneva: WHO; 2023. Available from: https://www.who.int/publications/i/item/9789240086173

2. White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet. 2014;383(9918):723-735. doi:10.1016/S0140-6736(13)60024-0

3. Dondorp A, Nosten F, Stepniewska K, Day N, White N; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366(9487):717-725. doi:10.1016/S0140-6736(05)67176-0

4. Dondorp AM, Fanello CI, Hendriksen IC, et al; AQUAMAT group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376(9753):1647-1657. doi:10.1016/S0140-6736(10)61924-1

5. Milne LM, Kyi MS, Chiodini PL, Warhurst DC. Accuracy of routine laboratory diagnosis of malaria in the United Kingdom. J Clin Pathol. 1994;47(8):740-742. doi:10.1136/jcp.47.8.740

6. Abba K, Deeks JJ, Olliaro PL, et al. Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries. Cochrane Database Syst Rev. 2011;(7):CD008122. doi:10.1002/14651858.CD008122.pub2

7. Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening malaria in African children. N Engl J Med. 1995;332(21):1399-1404. doi:10.1056/NEJM199505253322102

8. World Health Organization. Guidelines for the Treatment of Malaria. 3rd edition. Geneva: WHO; 2015. Available from: https://www.who.int/publications/i/item/9789241549127

9. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg. 2006;75(3):402-415.

10. Cox-Singh J, Davis TM, Lee KS, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008;46(2):165-171. doi:10.1086/524888

11. Checkley AM, Smith A, Smith V, et al. Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study. BMJ. 2012;344:e2116. doi:10.1136/bmj.e2116

12. Ashley EA, Dhorda M, Fairhurst RM, et al; Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371(5):411-423. doi:10.1056/NEJMoa1314981

13. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med. 1983;309(2):61-66. doi:10.1056/NEJM198307143090201

14. Maitland K, Kiguli S, Opoka RO, et al; FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495. doi:10.1056/NEJMoa1101549

15. Berkley JA, Bejon P, Mwangi T, et al. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis. 2009;49(3):336-343. doi:10.1086/600299

16. Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis. 2002;34(9):1192-1198. doi:10.1086/339909

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Exam-Focused Summary

Most High-Yield Facts for Exams

Epidemiology:

• 249 million cases, 608,000 deaths annually (76% children less than 5 years)
• P. falciparum: 99.7% of African malaria, most severe
• P. vivax: Most widespread geographically

Pathophysiology:

• P. falciparum: Cytoadherence (PfEMP1 → ICAM-1, VCAM-1, CD36) → sequestration
• Hypnozoites: Only P. vivax and P. ovale (dormant liver stage → relapses)
• Hemolysis: Direct, immune-mediated, splenic sequestration

Diagnosis:

• Thick film: Detection (sensitive)
• Thin film: Species ID, parasitemia quantification
• RDT: HRP2 (P. falciparum), pLDH (pan-Plasmodium); 95-99% sensitivity
• Three negative films needed to exclude

Severe Malaria (WHO Criteria - Know All 12):

1. Impaired consciousness (GCS less than 11)
2. Prostration
3. Multiple convulsions (> 2 in 24h)
4. Acidosis (pH less than 7.35 or lactate > 5)
5. Hypoglycemia (less than 40 mg/dL)
6. Severe anemia (Hb less than 7 adults, less than 5 children)
7. Renal impairment (Cr > 3 mg/dL)
8. Jaundice (bili > 3 mg/dL)
9. ARDS
10. Bleeding
11. Shock
12. Hyperparasitemia (> 10%)

Treatment:

• Severe: IV artesunate 2.4 mg/kg at 0, 12, 24h then daily (35% mortality reduction vs. quinine)
• Uncomplicated falciparum: ACT (artemether-lumefantrine or atovaquone-proguanil) × 3 days
• P. vivax/ovale: Chloroquine + primaquine 30mg daily × 14 days (CHECK G6PD FIRST)
• P. knowlesi: Treat as P. falciparum
• Pregnancy 1st trimester: Quinine + clindamycin; severe: IV artesunate (benefits >> risks)

Key Trials:

• SEAQUAMAT (2005): Artesunate vs. quinine in Asian adults - 35% mortality reduction
• AQUAMAT (2010): Artesunate vs. quinine in African children - 23% mortality reduction

Complications:

• Hypoglycemia: 8-50% (hourly monitoring essential)
• ARDS: 2-10% (40-80% mortality)
• Cerebral malaria: 15-25% mortality; 10-15% neurological sequelae
• Post-artesunate delayed hemolysis: 10-15% (monitor Hb weekly × 4 weeks)
• Lactate > 5 mmol/L: Strongest predictor of mortality

Prophylaxis:

• Atovaquone-proguanil: 1-2 days before, 7 days after (96-98% efficacy)
• Doxycycline: 1-2 days before, 28 days after (92-96%)
• Mefloquine: 2-3 weeks before, 4 weeks after (90-95%; neuropsychiatric effects)

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