Dengue Literature Review

Rajadhyaksha2012 - Dengue Evolving into SLE and Lupus Nephritis

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Rajadhyaksha2012 - Dengue Evolving into SLE and Lupus Nephritis

Full citation: Rajadhyaksha A, Mehra S. Dengue fever evolving into systemic lupus erythematosus and lupus nephritis: a case report. Lupus. 2012;21(9):999–1002. doi:10.1177/0961203312437807

Raw file: [[raw/rajadhyaksha2012.pdf]]

Summary

This case report describes a 22-year-old Indian woman with no prior medical history who developed dengue fever (DENV-1 primary infection) in June 2011 at KEM Hospital and Seth GS Medical College, Mumbai, Maharashtra, India. She presented with high-grade fever, skin rash, breathlessness, retro-orbital pain, arthralgias, and myalgias over 10 days. Laboratory investigations showed leucopenia, thrombocytopenia (platelet count 0.80 lac/mm³), haemoconcentration (haematocrit 48%), and elevated transaminases (SGPT 112, SGOT 98). Dengue IgM was positive by ELISA (16.27; threshold >11) and IgG negative, confirming primary infection. DENV-1 (genotype 1) was confirmed by RT-PCR. She was treated supportively and discharged.

Four weeks later (July 2011) she re-presented with recurrent fever, maculopapular facial rash, alopecia, generalised oedema, abdominal distension, and arthralgia. Blood pressure was 180/100 mmHg; anasarca was present. Investigations showed raised serum creatinine (5.0 mg%), hypoalbuminemia (albumin 2.0 g%), heavy proteinuria (6300 mg/24 hr), and urine microscopy with red blood cells, granular casts, and 3+ proteinuria. Ascitic fluid cytology showed serosanguinous fluid with LE cells. ANA by immunofluorescence was strongly positive (1:320 homogeneous, 4+), anti-dsDNA positive (1:80, 4+), C3 severely low (22 mg/dL; normal 90–180), and C4 low (5 mg/dL; normal 10–40). Anti-cardiolipin antibodies were elevated (IgM 44 MPLU/mL, IgG 12 GPLU/mL; both normal <8). ANCA and rheumatoid factor were negative. Renal biopsy showed diffuse proliferative glomerulonephritis grade IV — histologically confirmed ISN/RPS Class IV lupus nephritis.

She was treated with IV methylprednisolone 1 g/day for 5 days, then oral prednisolone 60 mg/day (tapered fortnightly), mycophenolate mofetil 1500 mg/day, hydroxychloroquine 400 mg/day, and antihypertensives. At 4-month follow-up, ANA and anti-dsDNA remained positive (unchanged titres), complement normalised, creatinine improved to 0.6 mg%, and 24-hr proteinuria fell to 1556 mg — partial but sustained renal response. Anti-cardiolipin remained elevated (IgM 46, IgG 18 at 4 months).

The authors propose that dengue viremia triggers excessive antibody production, leading to viral antigen–antibody immune complex deposition causing renal tubular damage and glomerulonephritis in susceptible individuals. They discuss the possibility that dengue infection unmasked subclinical SLE in a genetically predisposed individual, consistent with the established role of viral infections as lupus triggers. They claim this as the first published case of dengue fever evolving into lupus nephritis.

Study Design

  • Type: Case report — n=1 (lowest evidence level; not generalizable)
  • Sample size: n=1
  • Setting: KEM Hospital and Seth GS Medical College, Mumbai, Maharashtra, India; June–July 2011
  • Population: 22-year-old female with no prior autoimmune history

Key Findings

  • Dengue confirmed: DENV-1 by RT-PCR (genotype 1); IgM ELISA positive (16.27), IgG negative — primary infection
  • 4-week dengue→SLE interval: Autoimmune presentation emerged 4 weeks after dengue; no prior autoimmune history reported
  • Complete SLE autoantibody signature: ANA 1:320 homogeneous 4+; anti-dsDNA 1:80 4+; severely low C3 (22 mg/dL) and C4 (5 mg/dL)
  • Positive anti-cardiolipin (aCL): IgM 44 MPLU/mL and IgG 12 GPLU/mL at SLE diagnosis; persisting at 4 months (IgM 46, IgG 18) — a durable antiphospholipid response
  • Biopsy-confirmed Class IV lupus nephritis: Diffuse proliferative glomerulonephritis grade IV on renal biopsy
  • Ascitic fluid LE cells: Independent confirmation of lupus diagnosis
  • Treatment response: Partial renal response to methylprednisolone + MMF + hydroxychloroquine; serology positive throughout
  • Negative ANCA and RF: Excluding systemic vasculitis and rheumatoid overlap

Methods Used

Entities Mentioned

  • DENV-1 (confirmed infecting serotype by RT-PCR; primary infection)
  • Aedes aegypti (cited in discussion as primary dengue vector)

Concepts Addressed

Relevance & Notes

Rajadhyaksha2012 is the primary source for the “dengue→SLE+lupus nephritis” case cited in passing in Wan2012 - Autoimmunity in Dengue Pathogenesis as illustrative of dengue-triggered SLE. It provides the most detailed documented case in the wiki of a primary DENV-1 infection (confirmed IgM+/IgG-, RT-PCR positive) precipitating biopsy-confirmed ISN/RPS Class IV lupus nephritis within a 4-week interval, in a patient with no prior autoimmune history.

Critical limitation: No pre-dengue or acute-dengue autoantibody testing was performed. ANA and anti-dsDNA were not measured during the initial dengue hospitalisation in June 2011; the authors explicitly acknowledge this as a limitation. Consequently, it is impossible to determine whether dengue de novo generated autoimmunity (true triggering) or amplified pre-existing subclinical autoantibodies to clinical threshold (unmasking). The authors themselves favour the unmasking interpretation. This fundamental ambiguity limits the causal inference in the paper title (“dengue evolving into SLE”) — the timeline is suggestive but not probative.

Anti-cardiolipin persistence: Combined IgM + IgG aCL elevation persisting at 4 months is more prominent than the transient IgM aCL seen in Morel2014 - Autoimmune Response in Children With Dengue Case 1. Whether this represents dengue-induced transient antiphospholipid antibody (as seen in other viral infections) or nascent SLE-driven antiphospholipid syndrome (APS) is unclear; the 4-month persistence suggests SLE-driven rather than dengue-induced.

Comparison with Velazqueza2017 - SLE vs Dengue Case Series: Rajadhyaksha2012 has shorter dengue→SLE interval (4 weeks vs. 2 months for Velazqueza2017 Case 2), biopsy confirmation absent in Velazqueza2017, and confirmed primary infection. The Velazqueza2017 cases had higher ANA titres (1:1280 vs. 1:320) and antinucleosome antibodies (not measured here). Together, these cases strengthen the dengue-SLE association across independent settings.

Evidence weight: n=1 case report — cannot support generalizable claims about incidence, mechanism, or population-level risk.

Questions Raised

  • Were ANA and anti-dsDNA detectable at the time of acute dengue presentation? Without this datum, the causal direction (dengue triggering vs. dengue unmasking pre-existing subclinical SLE) cannot be resolved.
  • Are the persisting anti-cardiolipin antibodies dengue-induced or SLE-driven? The 4-month persistence distinguishes this from the transient antiphospholipid responses seen in other viral infections — but prospective APS follow-up is not reported.
  • ⚑ What immune deposits (IgG, IgM, complement, viral antigen?) were present in the renal biopsy immunofluorescence? The paper reports histological grade (Class IV) but not the immunofluorescence staining pattern — whether dengue viral antigen–antibody ICs (cf. Oishi2003/Saito2004 platelet IC deposition) or anti-nuclear ICs (classical lupus nephritis) drove the GN is completely undetermined. A study combining viral antigen immunostaining with standard lupus nephritis IF panel (IgG, IgM, C3, C4, C1q) in dengue-associated GN would directly resolve this mechanistic question.
  • Does the primary infection context (IgM+/IgG-) relate mechanistically to Vo2020’s finding that primary DENV-1 infection generates broader IgG autoantibody repertoires than secondary? Could primary infection specifically predispose to SLE triggering in genetically susceptible individuals?

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