What is the differential diagnosis for a patient with a rash and fever, potentially having underlying conditions such as diabetes (Diabetes Mellitus), hypertension (High Blood Pressure), or heart disease, and suspected of having dengue?

Differential Diagnosis for Dengue Fever

The differential diagnosis for dengue fever includes other flaviviruses (Zika, chikungunya), malaria, measles, rubella, leptospirosis, rickettsiosis, meningococcemia, group A streptococcal infections, and viral exanthems (parvovirus, adenovirus, enterovirus, hepatitis A), with testing approach determined by symptom duration and pregnancy status. 1, 2

Primary Infectious Disease Mimickers

Flavivirus Infections

• Zika virus is the most critical differential, particularly in pregnant women, requiring simultaneous NAAT testing for both dengue and Zika on serum collected ≤7 days after symptom onset 1, 2
• Chikungunya presents with similar fever, rash, and arthralgia but typically causes more severe joint pain 1, 3
• Cross-reactivity between flaviviruses (including West Nile virus, yellow fever, Japanese encephalitis) complicates serological diagnosis, making travel and vaccination history essential 4, 5

Bacterial Infections Requiring Urgent Differentiation

• Meningococcemia can initially present with maculopapular rash progressing to petechiae, mimicking dengue hemorrhagic fever, but progresses more rapidly and requires immediate antibiotic therapy 1, 6
• Leptospirosis shares fever, myalgia, and headache but typically includes conjunctival suffusion and biphasic fever pattern 1, 2
• Rickettsiosis (including Rocky Mountain spotted fever) presents with fever and rash on palms/soles, though this distribution occurs late in RMSF and in only half of cases 1
• Group A streptococcal infections can cause petechial rash after pharyngitis 1

Parasitic Infections

• Malaria must be excluded in any febrile traveler from endemic regions, particularly given overlapping geographic distribution with dengue 1, 2

Viral Exanthems

Common Viral Mimickers

• Measles and rubella present with fever and rash but have distinct prodromal symptoms and rash progression patterns 1, 2
• Parvovirus B19 causes "slapped cheek" appearance and lacy reticular rash, distinct from dengue's morbilliform pattern 1, 7
• Enterovirus infections (coxsackievirus, echovirus) can cause fever and maculopapular rash but typically occur in summer/fall in temperate climates 1
• Adenovirus presents with fever and rash but usually includes prominent respiratory or conjunctival symptoms 1, 2
• Hepatitis A shares fever, nausea, and elevated transaminases but typically includes jaundice and right upper quadrant pain 1, 2

Non-Infectious Conditions

Rheumatological and Autoimmune Disorders

• Systemic lupus erythematosus can present with fever, rash, thrombocytopenia, and elevated transaminases, particularly important to consider in patients with prolonged symptoms 6
• Kawasaki disease in children presents with prolonged fever, rash, and conjunctivitis 1

Hematological Conditions

• Immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura can mimic dengue hemorrhagic fever with petechiae and thrombocytopenia but lack fever and hemoconcentration 1, 8

Drug Reactions

• Drug hypersensitivity reactions can cause fever, rash (including palms/soles), and eosinophilia, requiring careful medication history 1, 7

Distinguishing Clinical Features

Key Dengue Characteristics

• Incubation period of 4-8 days after mosquito exposure in endemic area 4, 5
• Fever with retro-orbital pain, severe myalgia/arthralgia ("breakbone fever"), and positive tourniquet test 1, 4
• Biphasic rash pattern: initial flushing followed by morbilliform eruption appearing on days 3-5, often sparing palms/soles initially 7, 3
• Thrombocytopenia with hemoconcentration (rising hematocrit) distinguishes dengue hemorrhagic fever from dengue fever with unusual bleeding 8

Laboratory Clues

• Leukopenia with relative lymphocytosis and atypical lymphocytes supports dengue over bacterial infections 1, 8
• Elevated transaminases (2-5× normal) with normal bilirubin is common in dengue 4, 9
• Absence of thrombocytopenia significantly reduces dengue probability, making it a useful rule-out finding 4

Special Population Considerations

Pregnant Women

• Mandatory testing for both dengue and Zika virus by NAAT regardless of outbreak patterns due to risk of maternal death, hemorrhage, preeclampsia, eclampsia, vertical transmission, fetal loss, and microcephaly 1, 2, 5

Patients with Comorbidities

• Diabetes, hypertension, and heart disease increase risk of dengue hemorrhagic fever (AOR 2.16 for diabetes with hypertension) and warrant lower threshold for hospitalization 4, 9

Diagnostic Algorithm by Symptom Duration

Symptoms ≤7 Days

• Order dengue PCR/NAAT on serum as first-line test 4, 2, 5
• NS1 antigen detection serves as excellent alternative, detectable from day 1-10 after symptom onset 2, 5
• If NAAT negative, proceed to IgM antibody testing to avoid missing early infection 5
• Simultaneously test for Zika virus NAAT if epidemiologic risk exists 2

Symptoms >7 Days

• IgM capture ELISA becomes primary diagnostic test 4, 5
• Document complete vaccination history (yellow fever, Japanese encephalitis, tick-borne encephalitis) to interpret cross-reactive results 4
• Consider plaque reduction neutralization test (PRNT) if IgM positive to resolve false-positives from cross-reactivity 4, 5

Critical Pitfalls to Avoid

• Never dismiss dengue based solely on absence of rash, as up to 50% of cases lack the characteristic exanthem 3
• Do not prescribe NSAIDs or aspirin when dengue cannot be excluded due to increased bleeding risk 4
• Avoid delaying bacterial infection workup in severely ill patients with persistent fever and hemodynamic instability, as secondary bacterial infections occur in <10% but require prompt treatment 4
• Do not rely on single negative IgM test collected <7 days after onset, as this may reflect collection before antibody development 5