Santosa2012 - Delayed SLE Diagnosis Dengue Serology

Full citation: Santosa A, Poh Z, Teng GG. Delayed diagnosis of systemic lupus erythematosus due to misinterpretation of dengue serology. Scandinavian Journal of Rheumatology. 2012;41(1):77–79.

Raw file: [[raw/santosa2012.pdf]]

Summary

This is a letter to the editor comprising a single case report and a brief targeted review of dengue IgM serology performance in patients with pre-existing autoimmune conditions. The authors present a 20-year-old Malay man in Singapore whose SLE diagnosis was delayed because an initial positive dengue IgM was accepted as probable dengue fever, masking a multisystem autoimmune presentation. The case prompted the authors to systematically review the diagnostic properties of dengue serological tests with specific attention to patients with rheumatic diseases, and to propose a diagnostic algorithm.

The central mechanism proposed is bidirectional: (1) SLE generates ~120 autoantibodies from polyclonal B-cell activation, including low-affinity IgM species that can non-specifically bind dengue IgM test kit antigens, producing false-positive dengue IgM; and (2) immunosuppressive therapy and inherent adaptive immunity defects in established rheumatic disease can cause false-negative dengue serology in the event of true dengue infection. In endemic Singapore, the high index of suspicion for dengue in any febrile patient creates conditions where either false direction can delay the correct diagnosis.

Study Design

• Type: Case report + letter with targeted literature review (no original epidemiological data; single institution retrospective case)
• Sample size: n=1 (case), plus cited local kit validation data (RF-positive n=20; ANA-positive n=10; Panbio Dengue IgM/IgG immunochromatography kit)
• Setting: National University Health System (NUHS) and Singapore General Hospital, Singapore; dengue-endemic setting
• Population: 20-year-old Malay male, eventually diagnosed with SLE

Key Findings

• Case timeline: Patient presented with fever, rash, polyarthralgia, lymphopenia → positive dengue IgM → treated as probable dengue fever. Three weeks later: seizures, confusion, synovitis, thrombocytopenia (51 × 10⁹/L), ANA 1:320, anti-dsDNA 54 IU, anti-Ro, RF, hypocomplementemia — SLE diagnosed. Dengue IgM and IgG were negative at this second admission.
• False-positive confirmation: Lack of seroconversion of paired sera at 3 weeks supported false positivity of initial dengue IgM. True dengue infection would maintain IgM positivity for 8–12 weeks.
• Mechanism — polyclonal autoantibody load: ~120 SLE autoantibodies arise from polyclonal B-cell activation with mixed isotype, affinity, and avidity. Low-affinity IgM autoantibodies can non-specifically cross-bind dengue test kit antigens, producing false-positive dengue IgM results.
• Kit-specific false-positive rates (Panbio Dengue IgM/IgG immunochromatography, cited from manufacturer/local data):
  • RF-positive patients (n=20): 3/20 (15%) false-positive dengue IgM, 0/20 false-positive dengue IgG
  • ANA-positive patients (n=10): 0/10 false-positive dengue IgM or IgG — no cross-reactivity detected with this kit
• Commercial dengue IgM ELISA performance: sensitivity 62–99%, specificity 80–98%; cross-reactivity with other flaviviruses, malaria, leptospirosis, and RF can cause false-positive rates up to 70% (cited from Hunsperger et al. 2009 multi-kit evaluation).
• NS1 antigen: 92% sensitivity, 100% specificity within 9 days of illness — preferred for patients with known autoantibodies (non-immunological antigen detection avoids cross-reactive antibody interference).
• RT-PCR: Reliable within 5 days of fever onset; recommended in patients with autoantibodies.
• Bidirectional hazard: Immunosuppressive therapy in established rheumatic disease can cause false-negative dengue serology during true dengue infection — the case patient’s later fever was initially considered as a lupus flare; dengue IgM was positive but dengue IgG and NS1 antigen were negative (ultimately treated as lupus flare with good response).
• Proposed algorithm: Patients with pre-existing autoantibody-generating conditions (SLE, RA, malignancies) or atypical dengue course should be routed to RT-PCR (within 5 days) or NS1 antigen detection (within 9 days) rather than relying on dengue IgM alone.

Methods Used

• IgM-IgG Serology ELISA (Panbio Dengue IgM/IgG immunochromatography kit; false-positive rates in RF-positive and ANA-positive patients)
• NS1 Antigen Detection (cited as preferred test in autoantibody-positive patients; 92% sensitivity, 100% specificity within 9 days)
• RT-PCR (cited as reliable within 5 days of fever; non-immunological — unaffected by autoantibody interference)

Entities Mentioned

(No DENV-specific biological entities discussed — NS1 referenced as a diagnostic antigen only, not as a biological entity in its mechanistic context)

Concepts Addressed

• Autoimmunity in Dengue (bidirectional SLE-dengue diagnostic confusion; false serology in pre-existing SLE; diagnostic hazard in endemic settings)
• Antinuclear Antibodies (ANA 1:320 + anti-dsDNA in the case patient; low-affinity IgM autoantibodies as mechanism of false-positive serology; ANA-positive samples showed 0/10 cross-reactivity with Panbio kit)
• Infection-Triggered Autoimmunity (SLE potentially triggered or unmasked by dengue, discussed in passing; main focus is the reverse — pre-existing SLE affecting dengue diagnosis)

Relevance & Notes

This paper adds a practically important reverse diagnostic angle not previously documented in this wiki: pre-existing SLE autoantibodies can cause false-positive dengue IgM, delaying SLE diagnosis in endemic areas. All prior SLE-dengue cases in this wiki (Velazqueza2017, Rajadhyaksha2012, Morel2014, Palacios2016) address dengue triggering or co-presenting with SLE. Santosa2012 addresses the diagnostic system failure in the other direction.

The RF-positive 15% false-positive rate versus ANA-positive 0% cross-reactivity with the Panbio kit is mechanistically consistent with the low-affinity IgM explanation: RF is itself an IgM antibody against IgG Fc — a paradigm example of the low-affinity, cross-reactive IgM species that can bind dengue test antigens. ANA-associated antibodies in established SLE are predominantly IgG class (affinity-matured) and apparently do not cross-react with the Panbio kit at a detectable rate, though n=10 is insufficient to exclude rare false positives.

Limitations: n=1 case. The cited kit validation data (RF-positive n=20; ANA-positive n=10) are unpublished local figures from the authors’ institution — not peer-reviewed original research. The false-positive rate may vary by kit design and autoantibody profile. The conclusions about IgM vs. IgG autoantibody cross-reactivity are plausible but not tested experimentally.

Singapore geography: Third Singapore source (adds NUHS + SGH clinical context to the existing Seet2007 [NUH 2005 outbreak] and Palacios2016 [cites Chang 2007 retinal vasculitis]).

Questions Raised

• Is the 15% false-positive dengue IgM rate in RF-positive patients specific to the Panbio kit, or does it generalise across IgM capture ELISA platforms? The Hunsperger 2009 multi-kit evaluation found wide variability in cross-reactivity; kit-to-kit comparison in RF-positive patients would be clinically useful.
• The ANA-positive group showed 0/10 false-positives. But ANA-positive samples from dengue patients (not SLE) would have predominantly IgM-class non-specific IIFA reactivities (see Chatterjee2024 - ANA Detection in Dengue Kolkata). Would dengue-phase IgM ANA cross-react with dengue serology kits? This is a different question from SLE-IgG ANA cross-reactivity and has not been tested.
• What is the false-positive rate of dengue NS1 antigen tests (ELISA or RDT) in patients with high-titre antinuclear and anti-cytoplasmic IgG? NS1 is detected by antigen-antibody capture; non-immune antigen detection is theoretically unaffected by autoantibodies, but this has not been formally validated across the spectrum of SLE autoantibody loads.