Overview
Malaria
Quick Reference
Critical Alerts
- Plasmodium falciparum causes severe/cerebral malaria with high mortality
- Severe malaria is a medical emergency - mortality can exceed 20% even with treatment
- Artesunate IV is the drug of choice for severe malaria (superior to quinine)
- Parasitemia >2% with any severity marker indicates severe disease
- Consider malaria in ANY febrile patient with travel to endemic areas in past year
Key Diagnostics
- Thick and thin blood smears (gold standard)
- Rapid diagnostic test (RDT) for malaria antigens
- Parasitemia percentage (prognostic importance)
- CBC: Thrombocytopenia, hemolytic anemia
- BMP: Hypoglycemia, renal failure, metabolic acidosis
- Lactate for tissue perfusion assessment
Emergency Treatments
- Severe malaria: IV Artesunate 2.4 mg/kg at 0, 12, 24h, then daily
- Uncomplicated falciparum: Artemether-lumefantrine OR Atovaquone-proguanil
- Non-falciparum: Chloroquine (if sensitive) + Primaquine (for P. vivax/ovale)
- Supportive care: Glucose monitoring, fluid resuscitation, blood transfusion PRN
- Exchange transfusion: Consider if parasitemia >10% with severe disease
Definition
Malaria is a life-threatening parasitic disease caused by Plasmodium species transmitted by the bite of infected female Anopheles mosquitoes. It remains one of the world's most significant infectious diseases, with approximately 240 million cases and 600,000 deaths annually, predominantly in sub-Saharan Africa.
Plasmodium Species
| Species | Geographic Distribution | Severity | Unique Features |
|---|---|---|---|
| P. falciparum | Sub-Saharan Africa, SE Asia | Most severe | Cerebral malaria, high parasitemia |
| P. vivax | Asia, Americas, Africa | Moderate | Hypnozoites (relapses), enlarged spleen |
| P. ovale | West Africa | Mild | Hypnozoites (relapses) |
| P. malariae | Worldwide (tropical) | Mild | Long incubation, nephrotic syndrome |
| P. knowlesi | SE Asia (Malaysia, Borneo) | Moderate-Severe | 24-hour cycle, can be severe |
Epidemiology
- Global burden: 240+ million cases, 600,000+ deaths annually (WHO 2022)
- Endemic regions: Sub-Saharan Africa (>90% of deaths), SE Asia, South America, Pacific
- Imported malaria: ~2,000 cases/year in US, ~1,500/year in UK
- At-risk groups: Non-immune travelers, children <5 years, pregnant women
Transmission
- Vector: Female Anopheles mosquito (dusk to dawn biting)
- Incubation period: P. falciparum 7-14 days; P. vivax/ovale 12-18 days (up to months)
- Other transmission: Blood transfusion, congenital, needlestick (rare)
Pathophysiology
Parasite Life Cycle
In Mosquito (Sexual Cycle)
- Mosquito ingests gametocytes during blood meal
- Sexual reproduction in mosquito midgut
- Sporozoites migrate to salivary glands
In Human (Asexual Cycle)
- Hepatic stage: Sporozoites invade hepatocytes, multiply (1-2 weeks)
- Hypnozoites: P. vivax and P. ovale form dormant hepatic forms (cause relapses)
- Erythrocytic stage: Merozoites invade RBCs, replicate every 48-72 hours
- RBC rupture: Release of merozoites causes clinical symptoms
- Gametocytes: Some parasites develop into sexual forms
P. falciparum Pathophysiology
Cytoadherence
- Infected RBCs (iRBCs) express PfEMP1 proteins
- iRBCs adhere to endothelium in capillaries and venules
- Sequestration in vital organs (brain, kidneys, lungs)
- Explains why peripheral parasitemia underestimates total burden
Rosetting
- iRBCs bind to uninfected RBCs
- Contributes to microvascular obstruction
Consequences of Sequestration
- Microvascular obstruction → ischemia
- Blood-brain barrier disruption → cerebral edema
- Inflammatory response → cytokine storm
- Multi-organ dysfunction syndrome
Hemolysis and Anemia
- Direct RBC destruction by parasites
- Immune-mediated destruction of infected and uninfected RBCs
- Bone marrow dyserythropoiesis
- Splenic sequestration
Metabolic Derangements
Hypoglycemia (common and serious)
- Increased glucose consumption by parasites
- Quinine/quinidine-induced insulin release
- Impaired gluconeogenesis
Lactic Acidosis
- Anaerobic glycolysis due to sequestration
- Hepatic dysfunction
- Indicator of severe disease
Clinical Presentation
Classic Presentation
Malaria Paroxysm (classic but not always present)
- Cold stage: Rigors, chills (15-60 minutes)
- Hot stage: High fever (39-41°C), headache, tachycardia (2-6 hours)
- Sweating stage: Defervescence, diaphoresis, fatigue (2-4 hours)
Common Symptoms
Physical Examination
| Finding | Frequency | Notes |
|---|---|---|
| Fever | >0% | May be absent if recently treated |
| Pallor | Common | Anemia from hemolysis |
| Jaundice | 25-40% | Hemolysis and hepatic dysfunction |
| Hepatomegaly | 20-40% | More common in hyperreactive malaria |
| Splenomegaly | 20-50% | May be ruptured (rare) |
| Tachycardia | Common | Response to fever, anemia |
Severe Malaria (P. falciparum)
WHO Criteria for Severe Malaria
| Feature | Definition |
|---|---|
| Impaired consciousness | GCS <11 or BCS <3 |
| Prostration | Unable to sit/walk without support |
| Multiple convulsions | > in 24 hours |
| Acidosis | pH <7.25 or bicarbonate <15 mEq/L |
| Hypoglycemia | Glucose <40 mg/dL (<2.2 mmol/L) |
| Severe anemia | Hb <5 g/dL or Hct <15% in children; Hb <7 g/dL in adults |
| Renal impairment | Creatinine > mg/dL or urine output <400 mL/24h |
| Jaundice | Bilirubin >3 mg/dL with parasitemia >00,000/μL |
| Pulmonary edema/ARDS | O2 saturation <92%, respiratory distress, pulmonary edema on CXR |
| Significant bleeding | Including recurrent hemoglobinuria |
| Shock | SBP <80 mmHg (adults), impaired perfusion |
| Hyperparasitemia | >10% parasitemia or >00,000/μL |
Cerebral Malaria
Definition: Unarousable coma (GCS <11) in confirmed P. falciparum without other cause
Features
Organ-Specific Complications
Acute Kidney Injury
Pulmonary Complications
Hematological
Fever (almost universal)
Common presentation.
Headache (severe)
Common presentation.
Myalgias, arthralgias
Common presentation.
Malaise, fatigue
Common presentation.
Nausea, vomiting, diarrhea
Common presentation.
Abdominal pain
Common presentation.
Red Flags (Life-Threatening)
Critical Warning Signs
| Red Flag | Concern | Immediate Action |
|---|---|---|
| GCS <15 | Cerebral malaria | ICU, IV artesunate, neuroprotection |
| Parasitemia >% | High burden | IV artesunate, consider exchange transfusion |
| pH <7.35 or lactate > | Metabolic acidosis | Aggressive resuscitation |
| Glucose <70 mg/dL | Hypoglycemia | IV dextrose, frequent monitoring |
| Creatinine > mg/dL | Renal failure | Nephrology, consider RRT |
| Hb <7 g/dL | Severe anemia | Blood transfusion |
| SpO2 <92% | Respiratory failure | Oxygen, consider intubation |
| Seizures | Cerebral involvement | Benzodiazepines, phenytoin |
High-Risk Populations
| Population | Risk Factors |
|---|---|
| Non-immune travelers | No protective immunity |
| Returned VFR travelers | Often delay seeking care |
| Children <5 years | High mortality in endemic areas |
| Pregnant women | Severe anemia, adverse fetal outcomes |
| Asplenic patients | Overwhelming parasitemia |
| Immunocompromised | Increased severity |
Differential Diagnosis
Febrile Illness in Travelers
| Condition | Key Distinguishing Features |
|---|---|
| Dengue fever | Rash, severe headache, retro-orbital pain, thrombocytopenia |
| Typhoid fever | Gradual onset, relative bradycardia, rose spots |
| Viral hepatitis | Elevated transaminases, jaundice, GI symptoms |
| Leptospirosis | Conjunctival suffusion, muscle tenderness, exposure history |
| Rickettsial disease | Eschar, rash, headache |
| Chikungunya | Severe arthralgias, rash |
| Bacterial meningitis | Meningismus, photophobia |
| COVID-19 | Respiratory symptoms, anosmia |
| Influenza | Respiratory symptoms, myalgias, seasonal |
| HIV seroconversion | Rash, lymphadenopathy, pharyngitis |
Mimics of Severe Malaria
| Condition | Distinguishing Features |
|---|---|
| Bacterial sepsis | Positive cultures, no parasitemia |
| Meningoencephalitis | CSF abnormalities, negative smear |
| Viral hemorrhagic fever | Specific exposures, hemorrhagic manifestations |
| Heat stroke | Environmental exposure, dry skin, very high temp |
| Acute liver failure | Coagulopathy, transaminases markedly elevated |
Diagnostic Approach
Immediate Priorities
Any febrile patient with travel to endemic area in past year:
- Assume malaria until proven otherwise
- Obtain blood smear and RDT immediately
- Do not wait for results if severely ill - treat empirically
Laboratory Diagnosis
Blood Smear (Gold Standard)
| Test | Purpose | Details |
|---|---|---|
| Thick smear | Detection | More sensitive; lyses RBCs to concentrate parasites |
| Thin smear | Speciation | Morphology preserved; calculate parasitemia |
Parasitemia Calculation
- Light: <1% infected RBCs
- Moderate: 1-4%
- Heavy: >5% (severe disease indicator)
- Very heavy: >10% (consider exchange transfusion)
Rapid Diagnostic Test (RDT)
- Detects parasite antigens (HRP2 for P. falciparum, pLDH for all species)
- Sensitivity >95% for P. falciparum at parasitemia >100/μL
- May remain positive weeks after treatment
- False negatives possible at low parasitemia
Timing of Tests
- Parasites may not be detectable early in infection
- If negative, repeat smear every 12-24 hours x 3
- Never exclude malaria on single negative smear if high suspicion
Additional Laboratory Studies
| Test | Purpose | Findings in Severe Malaria |
|---|---|---|
| CBC | Anemia, thrombocytopenia | Low Hb, platelets often <100k |
| BMP | Electrolytes, renal function | Low glucose, elevated creatinine |
| LFTs | Hepatic function | Elevated bilirubin, transaminases |
| Coagulation | DIC screen | Prolonged PT/PTT in severe |
| Lactate | Tissue perfusion | Elevated in severe disease |
| ABG/VBG | Acidosis | Metabolic acidosis |
| Blood glucose | Hypoglycemia | Frequent monitoring required |
| Urinalysis | Hemoglobinuria | Dark urine, + blood without RBCs |
| Type and screen | Transfusion | May need blood products |
Imaging
- Chest X-ray if respiratory symptoms (ARDS, pulmonary edema)
- CT head if cerebral malaria (rule out other causes)
Treatment
Severe Malaria Treatment
First-Line: IV Artesunate
Loading dose: 2.4 mg/kg IV at 0, 12, and 24 hours
Maintenance: 2.4 mg/kg IV once daily thereafter
Duration: Until patient can take oral medication
Follow with: Complete course of oral ACT
If Artesunate Not Available: IV Quinidine
Loading dose: 10 mg/kg base IV over 1-2 hours
Maintenance: 0.02 mg/kg/min continuous infusion
Monitor: Continuous cardiac monitoring (QT prolongation)
Duration: Until parasitemia <1% and can tolerate oral
Follow with: Oral quinine + doxycycline/clindamycin
Adjunctive Management
| Issue | Management |
|---|---|
| Hypoglycemia | D50W boluses, D5-D10 infusion, check glucose hourly |
| Severe anemia | Transfuse pRBCs if Hb <7 g/dL or symptomatic |
| Seizures | Benzodiazepines, phenytoin/levetiracetam |
| Metabolic acidosis | Treat underlying cause, avoid bicarbonate |
| Acute kidney injury | Avoid nephrotoxins, early RRT if indicated |
| ARDS | Low tidal volume ventilation, conservative fluids |
| Cerebral edema | Elevate head, avoid hyperglycemia |
Exchange Transfusion Consider if:
- Parasitemia >10% in severe disease
- Parasitemia >5% with severe manifestations or not responding to therapy
- Removes parasitized RBCs and toxins
Uncomplicated Falciparum Malaria
First-Line: Artemisinin-Based Combination Therapy (ACT)
| Regimen | Dosing | Notes |
|---|---|---|
| Artemether-lumefantrine (Coartem) | 4 tablets BID x 3 days | Take with fat-containing food |
| Atovaquone-proguanil (Malarone) | 4 tablets daily x 3 days | Take with food |
| Dihydroartemisinin-piperaquine | Weight-based x 3 days | Avoid QT-prolonging drugs |
Alternative (if ACT unavailable)
- Quinine sulfate 650mg TID x 7 days + Doxycycline 100mg BID x 7 days
- Or Quinine + Clindamycin (if pregnant or child <8y)
Non-Falciparum Malaria
P. vivax, P. ovale (chloroquine-sensitive areas)
Chloroquine phosphate 1g (600mg base) initially
Then 500mg (300mg base) at 6, 24, and 48 hours
PLUS
Primaquine 30mg daily x 14 days (radical cure for hypnozoites)
Before Primaquine: Check G6PD status (causes hemolysis in G6PD deficiency)
P. malariae
- Chloroquine alone (no hypnozoites)
P. knowlesi
- Treat as P. falciparum (can be severe)
- ACT or IV artesunate if severe
Special Situations
Pregnancy
| Trimester | Treatment |
|---|---|
| First trimester | Quinine + clindamycin (avoid artemisinins if possible) |
| Second/third | ACT is acceptable |
| Severe disease | IV artesunate (lifesaving, benefits outweigh risks) |
Primaquine contraindications: Pregnancy, breastfeeding (if infant G6PD unknown), G6PD deficiency
Disposition
ICU Admission Criteria
- Any WHO criteria for severe malaria
- Altered mental status
- Parasitemia >5%
- Requiring IV artesunate
- Hemodynamic instability
- Respiratory distress
- Need for exchange transfusion
Ward Admission Criteria
- Uncomplicated falciparum malaria requiring observation
- Unable to tolerate oral medications
- Other concerning features (borderline labs)
- Social factors precluding safe outpatient management
Outpatient Management Criteria
Safe for Discharge
- Uncomplicated malaria (not falciparum) OR
- Uncomplicated P. falciparum with:
- Parasitemia <2%
- No severe malaria criteria
- Able to tolerate oral medications
- Reliable follow-up available
- Reliable patient/family
Follow-up Requirements
| Timeframe | Purpose |
|---|---|
| 24-48 hours | Clinical assessment, repeat smear |
| Day 3 (after treatment completion) | Confirm parasite clearance |
| Day 7 | Repeat smear to confirm cure |
| Day 28 | Late treatment failure screen |
| For P. vivax/ovale | Monitor for relapses up to 3 years |
Reporting
- Malaria is a notifiable disease in most countries
- Report to local public health department
Patient Education
Understanding Malaria
- Malaria is a serious infection caused by a parasite
- Transmitted by mosquito bites in tropical regions
- Can be fatal if untreated, especially P. falciparum type
- Complete treatment is essential even if feeling better
Medication Adherence
- Take ALL medications as prescribed - incomplete treatment leads to resistance
- Take artemether-lumefantrine with fatty food for better absorption
- Primaquine must be completed to prevent relapse (P. vivax/ovale)
- Report any side effects (nausea, vomiting, rash)
Warning Signs to Return
- Recurrence of fever
- Worsening headache, confusion
- Persistent vomiting, unable to keep medications down
- Dark urine
- Yellowing of eyes or skin
- Difficulty breathing
- Extreme weakness
Prevention for Future Travel
- Chemoprophylaxis: Start before, during, and after travel
- Personal protective measures:
- DEET-containing repellent
- Permethrin-treated clothing
- Long sleeves and pants at dusk/night
- Bed nets (insecticide-treated)
- Seek care early if fever develops within 1 year of travel
Special Populations
Pregnant Women
Risks
- Higher risk of severe disease
- Maternal anemia
- Placental malaria
- Preterm delivery, low birth weight
- Fetal loss
Management Modifications
- Lower threshold for admission
- Avoid primaquine (contraindicated)
- First trimester: Quinine + clindamycin preferred
- Second/third trimester: ACT acceptable
- Coordinate with obstetrics
Children
High-Risk Features
- Most deaths from malaria are in children <5 years
- Rapid progression to severe disease
- Hypoglycemia very common
- Seizures common in cerebral malaria
Dosing
- Weight-based dosing for all antimalarials
- IV artesunate 2.4 mg/kg (same as adults)
- ACT formulations available for children
Asplenic Patients
- Unable to clear parasitized RBCs effectively
- Risk of overwhelming parasitemia
- Lower threshold for aggressive treatment
- Prophylaxis especially important during travel
Returned Travelers
VFR (Visiting Friends and Relatives)
- Often do not take prophylaxis
- Believe they have immunity (incorrect if living in non-endemic area)
- May delay seeking care
- Education and counseling important
Quality Metrics
Performance Indicators
| Metric | Target |
|---|---|
| Blood smear within 4h of presentation | >5% |
| Treatment initiation within 1h for severe malaria | >0% |
| IV artesunate for severe malaria (if available) | 100% |
| Glucose monitoring (severe malaria) | Every 4 hours |
| Infectious disease/tropical medicine consult | All severe cases |
| Public health notification | 100% |
Documentation Requirements
- Travel history (countries, dates, prophylaxis use)
- Species identified (if known)
- Parasitemia percentage
- Severity classification
- Treatment regimen with timing
- G6PD status (before primaquine)
- Follow-up plan documented
Key Clinical Pearls
Diagnostic Pearls
- P. falciparum can be fatal within 48 hours in non-immune individuals
- Single negative smear does not exclude malaria - repeat x3
- Low platelet count is a sensitive (but nonspecific) finding
- Parasitemia underestimates total burden in P. falciparum (sequestration)
- Check for concurrent infections (travelers may have multiple diseases)
Treatment Pearls
- IV artesunate is superior to quinine for severe malaria (SEAQUAMAT, AQUAMAT trials)
- Check glucose frequently - hypoglycemia is common and recurrent
- Aggressive fluid resuscitation may worsen pulmonary edema - be cautious
- Primaquine for radical cure - but check G6PD first!
- Complete full course of oral therapy after IV artesunate
Disposition Pearls
- Admit all P. falciparum initially for monitoring (at minimum 24h)
- ICU for any severe malaria criteria - do not delay
- Smear at least 24h after treatment to confirm clearance
- Follow parasitemia to zero before concluding treatment success
- Report to public health - malaria is notifiable
References
- World Health Organization. Guidelines for malaria. 3rd edition. Geneva: WHO; 2022.
- Dondorp AM, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366(9487):717-25.
- Dondorp AM, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376(9753):1647-57.
- Centers for Disease Control and Prevention. Treatment of Malaria: Guidelines For Clinicians. Updated 2023.
- Trampuz A, Jereb M, Muzlovic I, Prabhu RM. Clinical review: Severe malaria. Crit Care. 2003;7(4):315-323.
- White NJ. The treatment of malaria. N Engl J Med. 1996;335(11):800-806.
Version History
| Version | Date | Changes |
|---|---|---|
| 1.0 | 2025-01-15 | Initial comprehensive version with 14-section template |