Malaria in 2025: A Comprehensive Guide for the Internist

Dr Neeraj MAnikath , claude.ai

Abstract

Malaria remains a critical global health challenge, with approximately 249 million cases reported in 2022. Despite advances in diagnostics and therapeutics, delayed recognition and inappropriate management continue to cause preventable mortality. This review provides practical guidance for internists on suspecting, diagnosing, and managing malaria in various clinical contexts, with emphasis on diagnostic pearls, therapeutic pitfalls, and emerging challenges including artemisinin resistance.

Introduction

Malaria, caused by Plasmodium species transmitted through Anopheles mosquitoes, affects primarily tropical and subtropical regions but increasingly presents in non-endemic areas due to global travel. Five species infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. P. falciparum accounts for the majority of severe cases and deaths, while P. vivax has the widest geographic distribution.

For internists, particularly those in non-endemic regions, the key challenge lies not in managing confirmed cases but in maintaining clinical suspicion. Missing malaria can be fatal; recognizing it early is lifesaving.

Clinical Suspicion: When to Think Malaria

The Travel History: Beyond the Obvious

Pearl #1: The "3-month rule" is outdated. While most P. falciparum cases present within 1 month of exposure, P. vivax and P. ovale can relapse months to years later due to dormant hepatic hypnozoites. The longest documented relapse for P. vivax occurred 30 years after exposure.

Clinical Hack: Ask three specific questions:

1. "Have you traveled to malaria-endemic areas in the past year?"
2. "Have you taken malaria prophylaxis? Which one, and did you complete it?"
3. "Have you had malaria before?" (Previous infection doesn't confer complete immunity)

Oyster #1: Not all "tropical" destinations are malarious. Major cities like Singapore, Hong Kong, and Dubai have no transmission. Conversely, malaria transmission occurs in areas patients might not consider risky: rural areas of Central America, Turkish-Syrian border regions, and even occasional airport-associated cases in Europe.

Clinical Presentation: The Great Mimicker

Classic paroxysmal fever (cold stage → hot stage → sweating stage) occurring every 48-72 hours is actually uncommon in non-immune adults. Most patients present with:

• Non-specific febrile illness (>90%)
• Headache (80%)
• Myalgias and arthralgias (60-70%)
• Gastrointestinal symptoms: nausea, vomiting, diarrhea (50-60%)
• Splenomegaly (20-40% in non-immune individuals)

Pearl #2: The "malaria triad" - Fever + Thrombocytopenia + Splenomegaly in a returned traveler has >95% positive predictive value for malaria in endemic area travelers.

Oyster #2: Malaria can present without fever. In one study, 8% of confirmed malaria cases in returned travelers were afebrile at initial presentation. If other features suggest malaria, test anyway.

High-Risk Populations Requiring Heightened Suspicion

• VFR travelers (Visiting Friends and Relatives): Immigrants returning to their country of origin have 8-10 times higher malaria risk than tourist travelers. They often underestimate risk and forgo chemoprophylaxis.
• Pregnant women: Malaria in pregnancy causes severe maternal anemia, fetal loss, and low birth weight
• Immunocompromised patients: Rapid progression to severe disease
• Asplenic patients: Risk of overwhelming parasitemia and rapid clinical deterioration

Diagnostic Approach

Laboratory Clues Before Confirmation

Pearl #3: The "thrombocytopenia signal" - Thrombocytopenia (platelet count <150,000/μL) occurs in 70-80% of malaria cases. In a febrile returned traveler, this should trigger immediate malaria testing.

Other suggestive laboratory findings:

• Anemia (often normocytic)
• Elevated LDH (hemolysis marker)
• Hyperbilirubinemia (indirect)
• Transaminitis (mild to moderate)
• Normal or low white blood cell count

Clinical Hack: Calculate the "platelet-to-WBC ratio." A ratio <10 has been shown to have good discriminatory value for malaria in febrile travelers.

Definitive Diagnosis

Gold Standard: Microscopy Thick and thin blood smears remain the gold standard. Thick smears detect parasites; thin smears identify species and quantify parasitemia.

Pearl #4: Timing matters. Parasitemia may be low or undetectable early in infection. If clinical suspicion is high with negative initial smears, repeat every 12-24 hours for at least 3 consecutive samples before excluding malaria.

Oyster #3: Never delay treatment in severe malaria waiting for parasitological confirmation. Treat empirically if suspicion is high.

Rapid Diagnostic Tests (RDTs) RDTs detect parasite antigens (HRP-2 for P. falciparum, pLDH for other species). Sensitivity: 95-100% at parasitemia >100 parasites/μL.

Limitations to remember:

• HRP-2 persists for weeks after treatment (cannot assess treatment response)
• pfhrp2/3 gene deletions in certain regions (East Africa, South America) cause false negatives
• May miss low-level parasitemia
• Don't quantify parasitemia

PCR: Most sensitive method (detects <5 parasites/μL) but not widely available and turnaround time limits acute management utility.

Clinical Hack: In resource-limited settings or when microscopy expertise is unavailable, RDTs are acceptable for initial diagnosis, but treatment decisions in severe malaria should never rely solely on RDTs.

Severity Assessment: Critical First Step

Classify every malaria case as uncomplicated or severe. This determines treatment location and regimen.

Criteria for Severe Malaria (Any ONE criterion):

Clinical manifestations:

• Impaired consciousness (GCS <11)
• Prostration (unable to sit/stand without assistance)
• Multiple convulsions (≥2 in 24 hours)
• Acute respiratory distress syndrome
• Circulatory collapse/shock
• Acute kidney injury (creatinine >3 mg/dL)
• Jaundice (bilirubin >3 mg/dL + parasitemia >100,000/μL)
• Abnormal bleeding
• Hemoglobinuria (blackwater fever)

Laboratory parameters:

• Severe anemia (Hb <7 g/dL)
• Hypoglycemia (glucose <40 mg/dL)
• Metabolic acidosis (pH <7.25 or bicarbonate <15 mmol/L)
• Hyperlactatemia (lactate >5 mmol/L)
• Hyperparasitemia (>5% in non-immune individuals)

Pearl #5: The "cerebral malaria paradox" - Impaired consciousness is not always proportional to parasitemia. Always investigate for other causes (meningitis, hypoglycemia) while treating for malaria.

Oyster #4: Acute kidney injury in malaria is often multifactorial: hemoglobinuria, hypovolemia, and cytokine-mediated injury. Aggressive fluid resuscitation may worsen pulmonary edema. Use caution.

Management

Uncomplicated P. falciparum or Species Unknown

First-line: Artemisinin-based Combination Therapy (ACT)

Standard regimens (3-day courses):

• Artemether-lumefantrine (Coartem®): Most widely available
  • Dose: Based on weight, given twice daily
  • Hack: Must be taken with fatty food (↑ lumefantrine absorption by 200%)
• Atovaquone-proguanil (Malarone®):
  • Dose: 4 tablets daily × 3 days
  • Advantage: Well-tolerated, can use in pregnancy (2nd/3rd trimester)
• Dihydroartemisinin-piperaquine
  • Longest post-treatment prophylactic effect

Pearl #6: Artesunate oral is NOT recommended for uncomplicated malaria in most settings due to high recrudescence rates when used as monotherapy. Always use combination therapy.

Alternatives (where ACTs unavailable):

• Quinine sulfate + doxycycline (or clindamycin if pregnant)
• Mefloquine (limited by neuropsychiatric side effects)

Oyster #5: In non-endemic settings, atovaquone-proguanil is often preferred due to its safety profile and excellent adherence (3-day regimen vs 7-day quinine-doxycycline).

Severe Malaria: Every Minute Counts

First-line: Intravenous Artesunate

• Dose: 2.4 mg/kg IV at 0, 12, and 24 hours, then daily until oral therapy tolerated
• Reduces mortality by 35% compared to quinine
• Critical Hack: Start immediately, even before species confirmation in any severely ill patient with suspected malaria

Alternative (if artesunate unavailable):

• Quinidine gluconate (USA) or quinine dihydrochloride (elsewhere) with cardiac monitoring

Pearl #7: The "artesunate availability problem" - In the US, IV artesunate is available through CDC for severe malaria but requires enrollment. Have your institution pre-register or know the 24-hour CDC Malaria Hotline: (770) 488-7788.

Adjunctive Management:

• ICU monitoring for severe cases
• Glucose monitoring (every 4 hours initially - quinine stimulates insulin release)
• Fluid management (cautious - risk of pulmonary edema)
• Transfusion for severe anemia (Hb <7 g/dL)
• Anticonvulsants if seizures occur (NOT prophylactically)
• Controversial: Exchange transfusion for hyperparasitemia (>10%) - limited evidence, reserved for critical cases where artesunate unavailable

Oyster #6: Steroids are NOT beneficial in cerebral malaria and may worsen outcomes.

Non-falciparum Malaria

P. vivax, P. ovale, P. malariae:

• Usually uncomplicated
• Chloroquine (25 mg base/kg over 3 days) remains effective in most regions
• Exception: Chloroquine-resistant P. vivax in Southeast Asia, Papua New Guinea - use ACT

Critical step for P. vivax and P. ovale: Add primaquine (or tafenoquine) to eradicate hepatic hypnozoites and prevent relapses

• Primaquine: 30 mg daily × 14 days (or 0.5 mg/kg/day)
• Tafenoquine: Single 300 mg dose (convenient but longer half-life)
• Essential: Check G6PD status before administration (risk of severe hemolysis in G6PD deficiency)

Pearl #8: In G6PD deficiency, primaquine can still be used at reduced dose (45 mg weekly × 8 weeks) under close monitoring.

Post-Treatment Considerations

Post-artesunate Delayed Hemolysis (PADH)

• Occurs 7-30 days post-treatment in 5-15% of patients
• Mechanism: Artesunate-exposed RBCs removed by spleen
• Monitor CBC weekly × 4 weeks after IV artesunate
• Usually self-limited but may require transfusion

Pearl #9: Counsel patients receiving IV artesunate to return for jaundice, dark urine, or fatigue within a month of treatment.

Emerging Challenges

Artemisinin Resistance

Partial artemisinin resistance (delayed parasite clearance) documented in Greater Mekong Subregion. Associated with kelch13 gene mutations. Not yet widespread in Africa, but vigilance required.

Practical implication: Treatment failures with ACTs should prompt investigation and may require alternative regimens (artesunate + mefloquine or triple-drug combinations in research settings).

Climate Change and Expanding Geographic Distribution

Rising temperatures are extending malaria transmission to higher altitudes and latitudes. Maintain suspicion even in traditionally non-endemic areas.

Prevention: Counseling the Traveler

Chemoprophylaxis options:

• Atovaquone-proguanil: Daily, 1-2 days before until 7 days after
• Doxycycline: Daily, 1-2 days before until 28 days after
• Mefloquine: Weekly, 1-2 weeks before until 4 weeks after

Pearl #10: The "adherence hack" - Atovaquone-proguanil's short post-exposure period dramatically improves completion rates compared to 4-week regimens.

Vector protection: DEET-based repellents, permethrin-treated clothing, bed nets, and staying indoors dusk-to-dawn remain crucial.

Conclusion

Malaria diagnosis requires a high index of suspicion in the appropriate epidemiological context. The combination of detailed travel history, recognition of clinical patterns, prompt diagnostic testing, and rapid initiation of appropriate therapy saves lives. Internists must remember that in the non-immune patient, progression from uncomplicated to severe malaria can occur within hours. When in doubt, test; when severe, treat immediately. The availability of highly effective treatments means that mortality from malaria in well-resourced settings should be exceedingly rare - every death represents a missed opportunity for diagnosis or delayed treatment.

Key References

1. World Health Organization. World Malaria Report 2023. Geneva: WHO, 2023.

2. Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med. 2008;358:1829-1836.

3. Lalloo DG, Shingadia D, Bell DJ, et al. UK malaria treatment guidelines 2016. J Infect. 2016;72:635-649.

4. Centers for Disease Control and Prevention. Treatment of Malaria: Guidelines for Clinicians (United States). Updated 2023.

5. Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Lancet. 2018;391:1608-1621.

6. 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;376:1647-1657.

7. Reyburn H. New WHO guidelines for the treatment of malaria. BMJ. 2010;340:c2637.

8. Rolling T, Agbenyega T, Krishna S, et al. Delayed hemolysis after artesunate treatment of severe malaria - Review of the literature. Am J Trop Med Hyg. 2015;92:697-701.

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