What is the overview of malaria, including transmission, risk factors, and treatment options for patients with a history of travel to tropical and subtropical regions?

Malaria Overview

Disease Fundamentals

Malaria is a potentially fatal mosquito-borne disease caused by Plasmodium parasites transmitted through the bite of infected female Anopheles mosquitoes, with P. falciparum being the most lethal species and responsible for the majority of deaths, particularly in sub-Saharan Africa. 1, 2

Causative Organisms

• Six Plasmodium species infect humans: P. falciparum, P. vivax, P. ovale wallikeri, P. ovale curtisi, P. malariae, and P. knowlesi 2
• P. falciparum accounts for approximately 79% of U.S. cases and causes the most severe disease with rapid progression to cerebral malaria, multi-organ failure, and death 3, 2
• P. vivax (11.2% of U.S. cases) and P. ovale form dormant liver hypnozoites causing relapsing infections weeks to months after initial treatment 2, 3
• P. knowlesi, a simian parasite prevalent in Southeast Asia, multiplies rapidly and can cause severe disease 2

Transmission Patterns

• Transmission occurs through bites of infected female Anopheles mosquitoes between dusk and dawn 1
• Less common routes include blood transfusion, congenital transmission from mother to fetus, and nosocomial exposure 1, 4
• Geographic distribution includes Central and South America, sub-Saharan Africa, the Indian Subcontinent, Southeast Asia, the Middle East, and Oceania 1, 5

Epidemiology and Risk Factors

U.S. Imported Malaria Patterns

• Approximately 2,000 cases diagnosed annually in the United States, with 82.4% occurring in adults and 78.6% in Black or African American individuals 3, 4
• Sub-Saharan Africa accounts for over 80% of imported U.S. cases, with West Africa alone responsible for 59.3% of cases 1, 4
• Among U.S. civilians, 77% of cases occur in those visiting friends and relatives in endemic areas 4
• Only 24.5% of U.S. residents with imported malaria reported taking any chemoprophylaxis, and 95% did not adhere to CDC-recommended regimens 4

High-Risk Travel Scenarios

• Travelers to sub-Saharan Africa face the highest risk, particularly in rural areas during evening and nighttime hours 1
• Backpackers and adventure travelers have higher exposure risk than tourists in air-conditioned hotels 1
• Longer-term residents without screened housing face greater risk than short-term visitors 1

Clinical Presentation

Typical Symptoms

• Fever with "flu-like" symptoms including chills, headache, myalgia, arthralgia, and malaise are the hallmark presentation 1, 6
• Approximately 50% of patients are afebrile at presentation despite having a history of fever 1
• Gastrointestinal symptoms (nausea, vomiting, diarrhea) and respiratory symptoms (cough) commonly occur 6
• Splenomegaly has a likelihood ratio of 6.6 for diagnosis 6
• Thrombocytopenia (<150,000/mL) occurs in 70-79% of patients and represents the most frequent laboratory abnormality 6

Severe Malaria Manifestations

• Severe malaria occurs in approximately 14% of U.S. cases, with a mortality rate of 0.3% 3
• Complications include cerebral malaria (confusion, seizures, reduced consciousness), kidney failure, pulmonary edema, severe anemia, metabolic acidosis, and shock 1, 6, 3
• P. falciparum can progress rapidly from uncomplicated to severe disease within hours 2
• Hypoglycemia may present with neurologic symptoms mimicking cerebral malaria 1

Incubation Periods

• Minimum incubation period is 6 days; most P. falciparum cases present within 1 month of return 1
• P. vivax and P. ovale can present up to 1 year or longer due to dormant liver hypnozoites 1
• P. malariae can persist asymptomatically in blood and present years after exposure 1
• Most patients (92.6%) develop symptoms within 90 days of returning from endemic areas 4

Diagnostic Approach

Critical Diagnostic Principles

• Any febrile patient with recent travel to an endemic area requires immediate malaria screening, as delayed diagnosis of P. falciparum increases mortality 6
• Direct microscopy of Giemsa-stained blood smears remains the reference standard for diagnosis 7
• A single negative blood smear cannot rule out malaria—three negative smears at 12-hour intervals are necessary to exclude the diagnosis 6
• Rapid diagnostic tests serve as important adjunctive tools but should not replace microscopy 7

Diagnostic Pitfalls to Avoid

• Do not rely on fever patterns, as most cases lack specific periodicity 1
• Do not exclude malaria based on chemoprophylaxis use, as adherence is typically poor 4
• Do not delay testing in afebrile patients with a history of fever and endemic area travel 1
• Consider malaria in pregnant women, as only 1 of 11 pregnant U.S. residents with malaria reported taking chemoprophylaxis 4

Treatment Strategies

Uncomplicated Malaria

• Artemisinin-based combination therapy is first-line treatment for uncomplicated P. falciparum malaria 3, 7
• Chloroquine remains an option only for P. falciparum acquired in known chloroquine-sensitive regions (e.g., Haiti) 3
• When artemisinin combinations are unavailable, use atovaquone-proguanil or quinine plus clindamycin for chloroquine-resistant malaria 3
• P. vivax, P. ovale, P. malariae, and P. knowlesi are typically chloroquine-sensitive and can be treated with artemisinin combinations or chloroquine 3
• P. vivax and P. ovale require additional therapy with an 8-aminoquinoline (primaquine or tafenoquine) to eradicate dormant liver hypnozoites and prevent relapses 3

Severe Malaria

• Intravenous artesunate is the first-line treatment for severe malaria and became FDA-approved and commercially available in 2020 3, 7, 4
• Life-threatening P. falciparum infections require immediate intravenous antimalarial therapy, followed by oral therapy to complete the course 8
• Local stocking of IV artesunate allows immediate treatment and provides the best chance for complete recovery without sequelae 4

Drug Resistance Considerations

• Chloroquine resistance in P. falciparum has spread to most malarious areas worldwide, including Africa 3
• Mefloquine resistance occurs predominantly in multi-drug resistant areas of Southeast Asia 8
• Cross-resistance exists between mefloquine and halofantrine, and between mefloquine and quinine in some regions 8
• In 2018, CDC analysis found resistance markers to pyrimethamine in 98% of specimens, sulfadoxine in 49.6%, chloroquine in 45.5%, and mefloquine in 2%, with no artemisinin resistance detected 4

Prevention for Travelers

Chemoprophylaxis Selection

• All travelers to malaria-endemic regions should take chemoprophylaxis before, during, and after travel 4
• Mefloquine is recommended for travelers at risk of chloroquine-resistant P. falciparum infection 1
• Alternative options for those unable to take mefloquine include doxycycline alone, or chloroquine with standby Fansidar treatment 1
• Begin prophylaxis one week prior to arrival in endemic areas 8

Mefloquine Precautions and Contraindications

• Mefloquine is contraindicated in patients with active depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders 8
• Neuropsychiatric symptoms (anxiety, depression, hallucinations, psychotic behavior) can occur and may persist for months or years after discontinuation 8
• Neurologic symptoms (dizziness, vertigo, tinnitus, loss of balance) may be permanent in some cases 8
• If psychiatric symptoms (acute anxiety, depression, restlessness, confusion, suicidal ideation) or neurologic symptoms occur, discontinue mefloquine immediately and substitute an alternative medication 8
• Avoid mefloquine in patients with epilepsy except for compelling medical reasons, as it increases seizure risk 8
• Do not administer halofantrine or ketoconazole with mefloquine or within 15 weeks of the last mefloquine dose due to risk of fatal QTc prolongation 8

Non-Pharmacologic Prevention

• Use protective clothing, insect repellents, and bed nets, as no chemoprophylaxis regimen is 100% effective 8
• Minimize outdoor exposure during dusk-to-dawn hours when Anopheles mosquitoes are most active 1
• Stay in air-conditioned or screened accommodations when possible 1

Special Populations

Pregnant Women

• Nineteen pregnant women were diagnosed with malaria in 2018, with only one of 11 U.S. residents reporting chemoprophylaxis use 4
• Artemisinin combination therapy should not be used in the first trimester of pregnancy for uncomplicated malaria 7
• Pregnant women traveling to endemic areas require careful counseling about risks and appropriate prophylaxis options 4

Children

• Neuropsychiatric symptoms from mefloquine can be difficult to identify in children, requiring vigilance especially in non-verbal children 8
• Children commonly present with fever, cough, headaches, malaise, vomiting, and diarrhea 6
• Children in Africa bear the highest mortality burden from malaria globally 7

Military Personnel

• Thirty-eight cases occurred among U.S. military personnel in 2018, representing 2.1% of total cases 4

Clinical Management Algorithms

For Returned Travelers with Fever

1. Immediately screen for malaria with blood smears if any travel to endemic areas within the past year 1, 6
2. Obtain three blood smears at 12-hour intervals if initial smear is negative but clinical suspicion remains high 6
3. Identify species and assess for severe malaria criteria (altered consciousness, seizures, respiratory distress, shock, jaundice, severe anemia, acidosis, high parasitemia) 3
4. If severe malaria: initiate IV artesunate immediately 3, 7
5. If uncomplicated malaria: use artemisinin-based combination therapy for P. falciparum or chloroquine for chloroquine-sensitive species 3
6. Add 8-aminoquinoline therapy for P. vivax or P. ovale to prevent relapses 3

For Pre-Travel Counseling

1. Assess destination-specific malaria risk by contacting CDC Malaria Hotline (770-488-7788 weekdays 9am-5pm ET, or 770-488-7100 after hours for urgent inquiries) 1, 4
2. Screen for psychiatric contraindications to mefloquine (depression, anxiety disorders, psychosis) 8
3. Prescribe appropriate chemoprophylaxis starting one week before travel 8
4. Educate on adherence: continue during travel and after leaving endemic area 4
5. Emphasize non-pharmacologic measures (protective clothing, repellents, bed nets) 8
6. Instruct to seek immediate medical attention for any fever during or after travel 6