What is the most likely diagnosis for a patient who develops an undulating (spiking-and-falling) fever every 48 hours shortly after returning from Central America?

Undulating 48-Hour Fever After Central America Travel: Malaria Until Proven Otherwise

The most likely diagnosis is malaria, specifically Plasmodium vivax or P. ovale, which characteristically produce fever spikes every 48 hours (tertian pattern) due to synchronized rupture of infected red blood cells. 1, 2

Why Malaria is the Leading Diagnosis

• Malaria accounts for 22.2% of all febrile illness in returning travelers and represents 67.7% of tropical disease diagnoses, making it the single most important infection to exclude urgently 1, 3

• The 48-hour fever periodicity is pathognomonic for P. vivax or P. ovale malaria (tertian fever pattern), occurring when mature schizonts rupture from erythrocytes in synchronized cycles 4

• Central America has endemic malaria transmission, particularly in rural areas of Guatemala, Honduras, Nicaragua, and Panama, with P. vivax being the predominant species in this region 1

• Malaria can rapidly progress to severe disease and death if untreated, particularly with P. falciparum, though P. vivax can also cause severe complications 1, 4

Immediate Diagnostic Approach

Obtain three thick and thin blood films over 72 hours (daily) immediately, as this is the gold standard for malaria diagnosis and species identification 3, 5, 6

• Do not wait for fever spikes to draw blood - parasitemia can be detected between febrile episodes, and delays in diagnosis increase mortality 5, 4

• Order a complete blood count with differential - thrombocytopenia (<150,000/μL) occurs in 70-79% of malaria cases and strongly predicts the diagnosis (likelihood ratio 2.9-11) 5, 2

• Check for additional predictive laboratory findings: hyperbilirubinemia (total bilirubin ≥1.3 mg/dL) has a likelihood ratio of 5.3-7.3 for malaria, and elevated LDH supports the diagnosis 2

• Physical examination should specifically assess for splenomegaly, which has the highest positive likelihood ratio (5.3-13.6) for malaria among clinical findings 1, 2

Critical Alternative Diagnoses to Consider

While malaria is overwhelmingly likely with this presentation, other infections must be considered if malaria is excluded:

• Dengue fever accounts for 15% of febrile travelers but typically presents with shorter fever duration (3-7 days) rather than undulating 48-hour cycles 1

• Enteric fever (typhoid/paratyphoid) represents 2.3% of febrile travelers and can present with fever patterns, but typically shows relative bradycardia and splenomegaly without the classic 48-hour periodicity 1, 3

• Leptospirosis can occur after freshwater exposure in Central America and accounts for 10% of febrile cases from Latin America in some series, but fever is typically continuous or remittent rather than periodic 1

Empiric Treatment Considerations

If clinical suspicion is high and the patient appears ill, empiric antimalarial therapy should be initiated while awaiting confirmatory testing 6

• Do not delay treatment for test results if severe malaria is suspected (altered mental status, respiratory distress, shock, jaundice, severe anemia, renal dysfunction, or parasitemia >5%) 4

• IV artesunate is the treatment of choice for severe malaria, though availability in the United States remains limited and requires CDC coordination 4

• For uncomplicated malaria, treatment depends on species identification and regional resistance patterns, but chloroquine remains effective for P. vivax from Central America in most cases 4

Common Pitfalls to Avoid

• Never assume "viral syndrome" or "flu" in a febrile traveler from malaria-endemic regions - this delay in diagnosis is the most common cause of preventable malaria deaths 7, 8, 9

• Do not rely on a single negative blood film to exclude malaria - sensitivity of a single film is only 50-75%, which is why three daily films are required 5, 7

• Do not assume adequate malaria prophylaxis excludes the diagnosis - inadequate chemoprophylaxis is actually a predictor of malaria, and breakthrough infections occur even with perfect adherence 2

• Alert laboratory staff when malaria is suspected to ensure appropriate processing and safety precautions 1

• Obtain blood cultures even when malaria seems likely, as enteric fever can coexist or present similarly and requires different treatment 3, 7