Differential Diagnosis of Dengue Fever
When evaluating a patient with suspected dengue fever, the differential diagnosis must include chikungunya, Zika virus, malaria, rubella, measles, hepatitis A, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsiosis, and group A streptococcal infections. 1
Clinical Presentation Requiring Differential Consideration
The classic dengue presentation includes fever with one or more of the following: nausea, vomiting, rash, headache, retro-orbital pain, myalgia, arthralgia, positive tourniquet test, or leukopenia 1. However, these symptoms overlap significantly with other infectious diseases, necessitating careful differentiation.
Key Differential Diagnoses by Clinical Features
Arboviral Infections:
- Zika virus presents with fever, rash, arthralgia, or conjunctivitis—overlapping substantially with dengue 1. For patients with possible exposure to both viruses, NAATs should be performed on serum collected ≤7 days after symptom onset 1.
- Chikungunya must be considered in the differential diagnosis, particularly in endemic regions 1.
Other Febrile Illnesses:
- Malaria should be excluded in any febrile patient returning from endemic areas 1.
- Leptospirosis can mimic dengue with fever, myalgia, and headache 1.
- Rickettsiosis presents similarly with fever and rash 1.
Viral Exanthems:
- Rubella and measles should be considered when rash is prominent 1.
- Parvovirus, adenovirus, and enterovirus can present with similar febrile syndromes 1.
Other Infections:
- Hepatitis A may present with fever and malaise 1.
- Group A streptococcal infections should be considered in the appropriate clinical context 1.
Diagnostic Approach to Differentiate Dengue
For patients presenting ≤7 days after symptom onset:
- Order dengue PCR/NAAT on serum as the preferred diagnostic method 2, 3.
- NS1 antigen detection serves as an excellent alternative, detectable from day 1 to day 10 after symptom onset 3, 4.
- Simultaneously test for Zika virus NAAT if there is risk for both infections 1.
For patients presenting >7 days after symptom onset:
- IgM antibody capture ELISA (MAC-ELISA) becomes the primary test, as IgM antibodies develop during the first week and remain detectable for 2-3 months 3.
- Dengue and Zika virus IgM antibody testing should be performed on NAAT-negative specimens 1.
Critical Diagnostic Pitfalls
Cross-reactivity with other flaviviruses (Zika, West Nile, yellow fever, Japanese encephalitis, tick-borne encephalitis) can complicate serological diagnosis 3. Document vaccination history to identify potential cross-reactivity 2.
Plaque reduction neutralization tests (PRNTs) provide improved specificity but are only available at select public health laboratories 3.
Special Population Considerations
Pregnant women must be tested by NAAT for both dengue and Zika viruses, regardless of outbreak patterns, due to risk of maternal death, hemorrhage, preeclampsia, eclampsia, vertical transmission, fetal loss, microcephaly, and serious birth defects 1, 2, 3.
Epidemiologic Context for Differential
Consider the patient's travel history and local outbreak patterns. During a dengue outbreak, jurisdictions may elect to forego Zika virus testing in nonpregnant persons with suspected dengue, though pregnant women should always receive comprehensive testing 1. The incubation period for dengue ranges from 3-14 days, with most cases developing symptoms 4-8 days after infection 3.
Neurological Complications
Dengue can present with neurological complications including Guillain-Barré syndrome, encephalopathy, acute motor weakness, seizures, and neuritis, occurring in 1-25% of cases 5. These complications should be considered when neurological symptoms develop during or after the acute febrile phase.