What are the differential diagnoses for a typical patient with suspected dengue presenting with acute fever, severe headache, retro‑orbital pain, myalgia, arthralgia, rash, nausea/vomiting, and possible thrombocytopenia?

Differential Diagnosis for Dengue Fever

The differential diagnosis for a patient with suspected dengue presenting with acute fever, headache, retro-orbital pain, myalgia, arthralgia, rash, and thrombocytopenia must include other arboviral infections (chikungunya, Zika), rickettsial diseases (scrub typhus, murine typhus, spotted fever), malaria, leptospirosis, influenza, and other viral syndromes—with geographic exposure history being the single most critical factor in narrowing the differential. 1

Primary Arboviral Infections to Consider

Chikungunya

• Presents with similar acute febrile illness but typically features more prominent and prolonged polyarthralgia/arthritis affecting small joints of hands, wrists, and ankles 1
• Incubation period is 2-3 days (range 1-12 days), slightly shorter than dengue 1
• Transmitted by the same Aedes mosquito vectors as dengue 1
• Geographic overlap with dengue throughout Asia, Africa, and increasingly reported in travelers returning to Europe 1
• Key distinguishing feature: arthralgia in chikungunya is typically more severe and can persist for weeks to months, whereas dengue arthralgia resolves with the acute illness 1

Zika Virus

• Clinical presentation overlaps significantly with dengue: fever, rash, myalgia, arthralgia, and conjunctivitis 1
• Incubation period is a few days to 2 weeks 1
• Most Zika infections are asymptomatic (similar to dengue), but when symptomatic, illness is typically milder than dengue with less prominent fever 1
• Critical to distinguish in pregnant women due to risk of microcephaly, fetal loss, and congenital abnormalities 1, 2
• Transmitted by Aedes mosquitoes but also sexually transmitted 1
• Testing approach: perform NAAT for both dengue and Zika simultaneously in pregnant women regardless of outbreak patterns 1, 2

Rickettsial Infections

African Tick Bite Fever (Rickettsia africae)

• Classic triad: fever, headache, myalgia with inoculation eschar, rash, and lymphadenitis (though each seen in <50% of cases) 1
• Incubation period 5-7 days (up to 10 days) 1
• Endemic throughout rural sub-Saharan Africa and eastern Caribbean 1
• Key distinguishing feature: presence of eschar at tick bite site, which is absent in dengue 1
• Common in travelers returning from safaris in southern Africa 1

Mediterranean Spotted Fever (Rickettsia conorii)

• Transmitted by dog ticks in urban/suburban Mediterranean areas, Middle East, Indian subcontinent 1
• More likely to cause complications than African tick bite fever, with reported mortality up to 4% 1
• Similar presentation to dengue but look for eschar and exposure to dogs or tick habitats 1

Murine Typhus (Rickettsia typhi)

• Found in tropical/subtropical port cities and coastal regions with dense rodent populations 1
• Transmitted by rat fleas 1
• Can be fatal with mortality rates up to 32% if untreated 1
• Majority of cases are mild but complications occur more frequently than with dengue 1

Scrub Typhus (Orientia tsutsugamushi)

• Significant cause of fever in rural south Asia (especially Laos), Southeast Asia, and western Pacific 1
• Transmitted by mite bites 1
• Reported mortality rate up to 32% in severe cases 1
• Infrequently reported in travelers but important consideration for those with rural exposure 1

Other Arboviral Infections

Yellow Fever

• Presents with hemorrhagic fever manifestations in severe cases 1
• Geographic restriction to specific endemic areas 1
• Vaccination history is critical: prior yellow fever vaccination can cause false-positive dengue IgM due to flavivirus cross-reactivity 2

Japanese Encephalitis

• Primarily presents with encephalitis rather than systemic febrile illness 1
• Consider in patients with neurologic symptoms and appropriate geographic exposure 1
• Prior vaccination causes cross-reactive antibodies with dengue serologic testing 2

West Nile Virus

• Can present as systemic febrile illness or encephalitis 1
• IgM antibodies can persist for months to years, complicating interpretation 1

Non-Arboviral Infectious Diseases

Malaria

• Must be excluded urgently in any febrile traveler from endemic areas 1
• Can present with fever, headache, myalgia similar to dengue 1
• Key distinguishing features: periodicity of fever, absence of rash, presence of rigors 1
• Requires immediate thick and thin blood smears 1

Leptospirosis

• Presents with fever, headache, myalgia (especially calf muscle pain), conjunctival suffusion 1
• Exposure history: freshwater contact, flooding, occupational exposure to animals 1
• Can cause hepatorenal syndrome in severe cases 1

Influenza

• Acute onset fever, headache, myalgia, but typically lacks rash and retro-orbital pain 1
• Respiratory symptoms more prominent than in dengue 1
• Seasonal patterns and exposure history helpful 1

Other Viral Syndromes

• Parvovirus, adenovirus, enterovirus can mimic dengue presentation 2
• Generally lack the severe thrombocytopenia and plasma leakage seen in dengue 2

Diagnostic Approach to Narrow the Differential

Critical History Elements

• Detailed travel itinerary including specific countries, cities, and rural vs. urban exposure within past 14 days 1, 2
• Complete vaccination history (yellow fever, Japanese encephalitis, tick-borne encephalitis) to interpret serologic cross-reactivity 2
• Mosquito bite exposure and use of protective measures 1
• Tick exposure, animal contact, freshwater exposure 1
• Sexual exposure history (for Zika consideration) 1

Laboratory Testing Strategy

• For symptoms ≤7 days: dengue NAAT/PCR on serum is preferred initial test 1, 2
• For symptoms >7 days: IgM capture ELISA becomes primary diagnostic test 1, 2
• If both dengue and Zika exposure possible: perform NAAT for both viruses simultaneously 1, 2
• Thick and thin blood smears to exclude malaria 1
• Complete blood count: thrombocytopenia and leukopenia support dengue but are not specific 1, 3
• Liver enzymes: SGOT > SGPT pattern is characteristic of dengue and helps differentiate from other viral infections 3

Key Distinguishing Clinical Features

• Presence of eschar strongly suggests rickettsial infection, not dengue 1
• Severe, prolonged polyarthralgia suggests chikungunya over dengue 1
• Conjunctivitis without purulent discharge suggests Zika 1
• Prominent respiratory symptoms suggest influenza 1
• Calf muscle pain with very elevated CPK suggests leptospirosis 4
• Retro-orbital pain, myalgia, and thrombocytopenia are significantly associated with dengue 3, 5

Common Pitfalls to Avoid

• Do not rely on single IgM result alone: false positives are common due to cross-reactivity with other flaviviruses (yellow fever, Japanese encephalitis, West Nile, Zika) 1, 2
• In secondary flavivirus infections, IgM response may be diminished and neutralizing antibodies against multiple flaviviruses rise rapidly, precluding conclusive determination 2
• Absence of thrombocytopenia significantly reduces probability of dengue and should prompt consideration of alternative diagnoses 2
• Do not assume dengue based on geographic exposure alone: chikungunya is increasingly common in same endemic areas 1
• Rickettsial infections require antibiotic therapy (doxycycline, fluoroquinolones, or azithromycin) and should respond within 24-48 hours; if no response, reconsider diagnosis 1
• In pregnant women, always test for both dengue and Zika regardless of local outbreak patterns due to severe fetal consequences 1, 2

When to Perform Confirmatory PRNT Testing

• When IgM is positive but cross-reactivity with other flaviviruses is suspected based on vaccination history 2
• When distinguishing dengue from Zika affects clinical management, particularly in pregnant patients 2
• PRNT titer ≥10 defines positive result with improved specificity over commercial serologic assays 2
• In primary flavivirus infections, neutralizing antibody titer ≥4-fold higher than other flaviviruses usually determines specific infecting virus 2