Farias2024 - Dengue Mimickers

Full citation: Farias LABG, Costa LB, Bessa PPN, Alcântara GFTA, Oliveira JL, Silva TN, Morais GFLM, Perdigão Neto LV, Cavalcanti LPG. Dengue Mimickers: Which Clinical Conditions Can Resemble Dengue Fever? Revista da Sociedade Brasileira de Medicina Tropical. 2024;57:e00206-2024.

Raw file: [[raw/Farias2024.pdf]]

Summary

This narrative review, written by seven Brazilian clinical experts (five infectious disease specialists, two rheumatologists, one epidemiologist), catalogues the full clinical differential diagnosis of dengue fever across five categories: infectious diseases, rheumatological conditions, hematological conditions, gastrointestinal conditions, and neurological conditions. The review is motivated by Brazil’s unprecedented 2024 dengue epidemic — over six million confirmed cases in the first six months, the worst in Brazilian history — which simultaneously raised dengue suspicion across the country while creating conditions for missed diagnoses of co-circulating conditions.

The core argument is that dengue’s broad symptomatic overlap with other febrile illnesses (infectious and non-infectious) creates two interrelated risks: underdiagnosis of dengue (other diagnoses mistaken for it), and overdiagnosis (dengue diagnosed when another condition is present). Both risks carry outcome consequences: delayed antibiotic treatment in meningococcemia; unnecessary surgical intervention in dengue presenting as acute abdomen; missed immunosuppression in SLE or Still’s disease; and false reassurance when a treatable infection is categorised as dengue during an epidemic. The paper references Santosa2012 - Delayed SLE Diagnosis Dengue Serology and the Li2018 - Increased Risk of Autoimmune Diseases in Dengue Taiwan cohort data explicitly, situating this review within the broader dengue-autoimmunity literature.

Study Design

• Type: Narrative review (expert consensus, no systematic search)
• Sample size: N/A (review; no original patient data)
• Setting: Institutions in Fortaleza (Ceará) and São Paulo (São Paulo state), Brazil; databases searched: LILACS, PubMed, Google Scholar
• Population: N/A; clinical cases used illustratively from authors’ institutional experience

Key Findings

Infectious Disease Mimickers

• Meningococcemia: Early fever + petechial rash indistinguishable from dengue; as meningococcemia progresses, violaceous/necrotic skin lesions emerge; coinfection with DEN and Neisseria meningitidis documented with fatal outcome during Rio de Janeiro 2023 outbreak; if uncertain, empirical ceftriaxone 2 g/day recommended immediately to prevent bacterial fatality
• Malaria: Low platelet count + anemia shared with dengue; chills, sweating, travel history (especially Amazonian regions), tertiary/quartan fever pattern distinguish malaria; thick blood smear is key in endemic areas; coinfections documented in Amazon (2.8% of 1,578 acute fever patients)
• COVID-19 vs. dengue: Dyspnea strongest predictor of COVID-19 (not dengue); anosmia pathognomonic for COVID-19; dengue distinguished by retro-orbital pain, rash, petechiae, bleeding; both trigger cytokine storm; both can cause myositis with elevated CK
• Arboviruses (CHIKV, ZIKV, YFV, OROV, MAYV, WNV): All share acute febrile onset with dengue; key differentiators:
  • CHIKV: more intense polyarthralgia/arthritis, post-acute chronic phase; ~6% serological cross-reactivity with dengue
  • ZIKV: low/absent fever (contrast with dengue), conjunctivitis; high flavivirus serological cross-reactivity with dengue (ZIKV and DENV both flaviviruses)
  • YFV: jaundice, hepatic damage; epidemiological competition with DENV hypothesised (mosquito co-infection exclusion)
  • OROV: near-identical presentation to dengue; 448.86% case increase in Brazil 2024; spread beyond Amazon to all macroregions
  • MAYV: intense polyarthralgia differentiates from dengue; co-circulation with CHIKV in Amazon region
• Leptospirosis: Calf myalgia, conjunctival suffusion, jaundice distinguish it from dengue; CRP >50 mg/L identified as biomarker favoring leptospirosis over dengue; delayed antibiotic treatment in missed leptospirosis increases mortality
• Mono-like infections (EBV, CMV, HIV, Toxoplasma): Thrombocytopenia + elevated CRP shared with dengue; post-amoxicillin rash distinguishes EBV from dengue defervescence rash; case of false-positive EBV heterophile test in returning dengue traveler documented

Rheumatological Mimickers

• SLE: Classic bidirectional confusion — SLE flare and dengue share fever, arthralgia, myalgia, rash, thrombocytopenia, lymphopenia, transaminase elevation; reports of SLE misdiagnosed as dengue and dengue misdiagnosed as SLE; DEN serology false-positive in SLE/RA: commercial dengue IgM kits cross-react with lupus autoantibodies, RF, and malaria; RT-PCR within first 5 days is the gold standard discriminator; NS1 antigen 92% sensitivity, 100% specificity within 5 days; anti-DNA and complement levels aid SLE identification; Santosa2012 diagnostic algorithm explicitly recommended
• RA: DEN presents polyarthralgia/myalgia/myositis but without synovitis (which RA presents); synovitis absence is the key differentiating feature; exposure to dengue does not increase RA risk (Malaysian epidemiological study)
• Still’s disease: High-spiking fever, arthralgia, evanescent salmon-colored rash vs. dengue defervescence exanthema (blanches under pressure); markedly elevated ferritin, leukocytosis, neutrophilia, absence of RF/ANA in Still’s vs. anemia/lymphopenia/thrombocytopenia in dengue
• Post-dengue autoimmune triggers (Li2018 Taiwan cohort, n=12,506): Significantly elevated risks of Reiter’s syndrome (aHR 14.03), multiple sclerosis (aHR 11.57), myasthenia gravis (aHR 5.35), autoimmune encephalomyelitis (aHR 3.80), systemic vasculitis (aHR 3.70), SLE (aHR 3.50), primary adrenocortical insufficiency (aHR 2.05) — corroborating the autoimmune sequelae thread
• Dengue triggering specific autoimmune conditions:
  • Necrotizing immune-mediated myopathy: triggered in 9-year-old boy with high CPK (30,833 mg/dL); juvenile dermatomyositis excluded (no rash)
  • Sacroiliitis: case of unilateral sacroiliitis following dengue in young woman; coincidental co-occurrence could not be ruled out
  • Kawasaki disease (KD): dengue is a recognised KD trigger in endemic regions; suspect KD when dengue fever prolongs alongside “strawberry tongue”, finger desquamation, conjunctival injection, cervical lymphadenopathy, thrombocytosis
  • Multisystem inflammatory syndrome in children (MIS-C): distinguished from severe dengue by higher CRP, conjunctival injection, oral mucosal changes; dengue has higher Hb/Hct, lower platelets, greater aminotransferase elevation

Hematological Mimickers

• ITP: Isolated thrombocytopenia without lymphopenia, without high Hct, without viral syndrome should raise suspicion of ITP rather than dengue; absence of fever valuable early discriminator; dengue may co-occur with ITP as a comorbidity or trigger ITP; fatal DENV-4 case in Brazil in ITP patient documented
• TTP: Thrombocytopenia + neurological symptoms (headache, disorientation) can mimic dengue; low platelet + anemia overlap; ADAMTS13 deficiency distinguishes TTP
• Myelodysplastic syndrome (MDS): Thrombocytopenia + anemia during dengue outbreak may mimic severe dengue; clonal bone marrow disease with morphological dysplasia distinguishes
• Other hematological conditions: Plasmacytosis ≥20% suggests plasma cell leukemia/myeloma — not a dengue feature despite fever and thrombocytopenia overlap

Gastrointestinal/Other Mimickers

• Acute abdomen: Dengue can present as acute abdomen in ~12% of cases (Pakistan data); presentations mimic acute cholecystitis, appendicitis, pancreatitis, splenic rupture; misdiagnosis leading to unnecessary surgery documented — DEN patients with thrombocytopenia who undergo surgery are at high hemorrhagic risk; gallbladder wall thickening (GBWT) >3mm on ultrasound is a useful DHF marker: one study found 90.5% sensitivity, 69.6% specificity; another found GBWT 100% sensitivity for determining ICU vs. ward admission at 62.1% specificity; ultrasound should not be used as screening (low sensitivity for ruling out)
• Cardiac: Dengue myopericarditis can mimic acute myocardial infarction (ST elevation, chest pain) in young adults; arrhythmias documented

Neurological Mimickers/Complications

• Prevalence of dengue neurological complications: Encephalopathy/encephalitis documented in 0.5–6.2% of dengue patients; hemorrhagic stroke in 0.06–0.26% of hospitalised dengue patients
• CNS symptoms: Headache (>97% of dengue patients), insomnia, dizziness, altered mental status, seizures, meningitis, muscle weakness; EEG may show burst suppression, electrographic seizures; neuroimaging may show diffuse cerebral edema or appear normal (no specific MRI features for dengue encephalitis)
• Post-infectious immune-mediated syndromes: Mononeuropathies, GBS, brachial neuritis, transverse myelitis, ADEM, acute cerebellitis, opsoclonus-myoclonus syndrome, optic neuritis, parkinsonism
• Dengue myositis: Cytokine-mediated muscle cell injury; rhabdomyolysis → renal damage; hypokalemia → acute flaccid quadriplegia without cranial nerve palsy
• Distinguishing from primary headache disorders: Fever + myalgia + rash always raise dengue suspicion over primary headache in endemic settings

Brazil Epidemiology 2024

• 2024 epidemic: >6 million cases reported in the first six months — described as the worst dengue epidemic in Brazil’s history
• All serotypes (DENV-1 through DENV-4) circulate in Brazil; OROV, CHIKV, ZIKV, MAYV, and YFV co-circulate, complicating differential diagnosis
• Brazil has >200 described arboviruses; flavivirus cross-reactivity in serology complicates regional diagnosis
• RT-qPCR Multiplex tests simultaneously identifying DENV/ZIKV/CHIKV are available in official laboratories during epidemics but not all patients undergo confirmatory testing

Methods Used

• NS1 Antigen Detection — reviewed as gold-standard early test; 92% sensitivity, 100% specificity within first 5 days
• RT-PCR — preferred within first 5 days; gold standard for differentiation from SLE and arbovirus coinfections
• IgM-IgG Serology ELISA — cross-reactivity issues reviewed extensively; false-positive in SLE, RA, leptospirosis, malaria; CHIKV ~6% cross-reactivity; ZIKV/YFV high cross-reactivity

Entities Mentioned

• Aedes aegypti — primary vector for DENV, CHIKV, ZIKV, YFV; co-transmission of multiple viruses in single bite documented
• Aedes albopictus — more effective vector for CHIKV; co-transmits DENV and CHIKV independently
• DENV-1, DENV-2, DENV-3, DENV-4 — all four serotypes circulating in Brazil 2024
• NS1 Protein — diagnostic target; NS1 antigen test used as discriminator in SLE-dengue overlap

Concepts Addressed

• Autoimmunity in Dengue — SLE-dengue bidirectional confusion; dengue triggering autoimmune conditions; ITP link; KD and MIS-C differentiation
• Dengue Pathophysiology — acute abdomen (~12% of cases); gallbladder wall thickening as DHF ultrasound marker; two hypotheses for dengue pancreatitis (autoimmune vs. direct viral invasion)
• Dengue Neurological Complications — encephalopathy/encephalitis 0.5–6.2%; hemorrhagic stroke 0.06–0.26%; comprehensive list of post-infectious immune-mediated syndromes
• Cross-Reactive Antibodies — CHIKV ~6% cross-reactivity with dengue serology; ZIKV/YFV high flavivirus cross-reactivity; false-positive dengue IgM in SLE/RA/malaria/leptospirosis
• Dengue Clinical Classification — differential diagnosis framing across all severity levels; warning signs in differential context
• Infection-Triggered Autoimmunity — dengue triggering necrotizing myopathy, sacroiliitis, KD
• Cytokine Storm — shared mechanism between dengue and COVID-19; both trigger cytokine-mediated complications

Relevance & Notes

Farias2024 is the first dedicated dengue differential diagnosis review in this wiki. Its primary contribution is clinical orientation: it systematically maps the conditions that mimic dengue (and vice versa), which has direct relevance to the autoimmunity thread — the SLE-dengue confusion documented here is the real-world clinical context in which Santosa2012’s diagnostic algorithm matters. The paper explicitly cites Santosa2012’s algorithm and the Li2018 Taiwan cohort data (the same cohort already ingested into this wiki as Li2018 - Increased Risk of Autoimmune Diseases in Dengue), confirming that the dengue-autoimmune risk signal has reached clinical differential diagnosis literature.

As a narrative review by clinical experts, this paper should be weighted appropriately — it synthesises others’ data rather than reporting original findings. The specific numbers it quotes (NS1 92%/100%, GBWT sensitivity/specificity, 0.5-6.2% encephalopathy prevalence) come from cited primary sources, not from this paper’s own data.

The 2024 Brazil epidemic context (>6 million cases) makes this a useful epidemiological anchor for the Brazilian dengue situation — the most current available data for Brazil in this wiki.

Questions Raised

• Dengue co-infection with OROV, MAYV, or other Brazilian arboviruses: how frequently do coinfections occur, and do they worsen dengue severity? The 2.8% coinfection rate in the Amazon Magalhães study suggests substantial real-world overlap.
• Is Still’s disease ever triggered by dengue (as opposed to merely mimicking it), analogous to the dengue-ITP and dengue-KD triggering relationships? No case of dengue-triggered Still’s disease (adult-onset) is referenced here.
• The gallbladder wall thickening >3mm finding needs validation across settings: two studies cited show conflicting sensitivity ranges (90.5% vs. 58%) — is this a reliable clinical decision tool or setting-dependent?