Dengue Literature Review

Morel2014 - Autoimmune Response in Children With Dengue

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Morel2014 - Autoimmune Response in Children With Dengue

Full citation: Morel Z, Ramírez A. Autoimmune Response in Children With Dengue. Case Reports. Reumatol Clin. 2014;10(4):257–259. https://doi.org/10.1016/j.reumae.2014.03.008

Raw file: [[raw/Morel2014.pdf]]

Summary

This case series reports three pediatric patients presenting to a Paraguayan referral hospital during endemic dengue transmission, each developing clinically significant autoimmune or immune-mediated complications attributable to dengue virus (DV) infection. Paraguay is described as having endemic dengue with hyperimmune responses. The three cases span two distinct clinical syndromes: a self-limiting case with partial autoimmune markers but no standard antinuclear antibodies (Case 1), and two cases fulfilling criteria for macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH) (Cases 2 and 3). The paper uses MAS and secondary HLH interchangeably for the latter two cases, applying the HLH-2004 diagnostic protocol (5 of 8 criteria without bone marrow hemophagocytosis).

Critically, ANA and anti-dsDNA were negative in all three cases — including both MAS cases. The authors propose molecular mimicry, cell activation, and viral persistence as candidate mechanisms, but the ANA-negative pattern in the most severe cases conflicts with the assumption that dengue-associated autoimmunity necessarily involves ANA production. The paper’s principal contribution is establishing MAS as a dengue complication that operates through a mechanism distinct from the NS1 molecular mimicry → antinuclear antibody pathway.

Study Design

  • Type: Case series / case report
  • Sample size: 3 patients
  • Setting: Hospital Central del Instituto de Previsión Social, Asunción, Paraguay; endemic dengue country
  • Population: Pediatric patients (8 years, 3 years, 3 months); all male

Key Findings

Case 1 (8-year-old male):

  • Fever for 8 days, abdominal pain, joint pain, hepatosplenomegaly, bilateral pleural effusion, retroperitoneal lymphadenopathy
  • DV confirmed: IgG and IgM antibody isotypes both positive (suggesting reinfection or early primary with cross-reactive IgG from maternal transfer)
  • Autoimmune labs: ANA negative, anti-dsDNA negative, lupus anticoagulant negative; IgM anticardiolipin antibodies POSITIVE
  • C3 and C4 normal; hypocomplementemia (reported in text); proteinuria with hypoalbuminemia; bicytopenia (leukocytes 2500/ml, platelets 80,000/mm³)
  • Self-limiting: resolved without treatment; discharged in good condition

Case 2 (3-year-old male):

  • Fever for 7 days with skin lesions (erythematous macules, universal petechiae), abdominal pain, hepatosplenomegaly, condensation on right lung base, minimal pericardial effusion (echocardiography), free abdominal fluid
  • DV confirmed: NS1 antigen positive
  • Autoimmune labs: ANA negative, anti-dsDNA negative, rheumatoid factor negative, febrile antigens negative
  • Bone marrow aspirate: normal (no hemophagocytosis)
  • MAS criteria met: fever, leukopenia with neutropenia (3000 leukocytes/ml, 900 neutrophils/ml), anemia (Hgb 8.2 g/dl), hepatosplenomegaly, triglycerides 470 mg/dl, hyperferritinemia 1150 mg/dl
  • Treatment: Methylprednisolone boluses → clinical improvement; fever, jaundice, and organomegaly resolved; discharged

Case 3 (3-month-old infant, male):

  • Fever for 4 days, vomiting, diarrhea, hepatosplenomegaly, thickened gallbladder wall, free abdominal fluid (ultrasound)
  • DV confirmed: NS1 antigen positive
  • Autoimmune labs: ANA negative, anti-dsDNA negative, rheumatoid factor negative, febrile antigens negative
  • Bone marrow aspirate: normal (no hemophagocytosis)
  • MAS criteria met: fever, hepatosplenomegaly, leukopenia with neutropenia (3500 leukocytes/ml, 1100 neutrophils/ml), anemia (Hgb 8.0 g/dl), hypertriglyceridemia 383 mg/dl, hyperferritinemia 3828 mg/dl
  • Treatment: Methylprednisolone boluses → clinical improvement, decreased visceromegaly, hematologic recovery; discharged

Key cross-case patterns:

  • ANA and anti-dsDNA negative in all three cases — the most severe (MAS) cases had NO conventional antinuclear autoantibodies
  • Only anticardiolipin IgM was positive — and only in the mildest case (Case 1)
  • Both MAS cases responded favorably to corticosteroids without bone marrow hemophagocytosis (fulfilled 5 of 8 HLH-2004 criteria by other parameters)
  • NS1 positivity confirmed dengue in Cases 2 and 3; antibody serology confirmed in Case 1

Methods Used

Entities Mentioned

(Serotype not specified in any of the three cases — DV diagnosed generically by NS1 antigen and serology; no specific DENV-1/DENV-2/DENV-3/DENV-4 entity link applies.)

Concepts Addressed

Relevance & Notes

This paper establishes a critically important negative finding for the wiki’s autoimmunity thread: ANA was negative in all three cases, including the two most severe (MAS). The existing wiki literature (Lin2006, Lin2011, Wan2012, Chatterjee2024, Garcia2009) largely frames dengue autoimmunity through the lens of antinuclear antibodies, anti-platelet, and anti-endothelial antibodies. Morel2014 shows that the most severe autoimmune complication in this series occurred without these markers.

The apparent inversion within the case series is notable: Case 1 (the mildest, self-limiting case) had the most autoimmune markers (anticardiolipin IgM, hypocomplementemia, proteinuria), while Cases 2 and 3 (the most severe, requiring corticosteroids) had no detectable standard autoantibodies. This does not necessarily reverse the Wan2012 autoantibody-severity correlation, because Wan2012 measured anti-endothelial/platelet antibodies by flow cytometry (not standard ANA/anti-dsDNA), and MAS is mechanistically driven by macrophage/CD8+ T cell hyperactivation rather than autoantibody-mediated damage.

Palacios2016 (a letter to the editor responding to this paper) adds literature context but does not resolve this mechanistic distinction.

Limitation: Case series with no control group; serotypes not specified; ANA method not specified (assumed standard ELISA or IIFA); small sample in a single tertiary centre.

Questions Raised

  • Does dengue-triggered MAS/HLH represent a fundamentally different immunological mechanism than the NS1 mimicry → autoantibody pathway (macrophage CD163 hyperactivation vs. cross-reactive B cell stimulation)?
  • Would these MAS cases have shown elevated anti-endothelial or anti-platelet antibodies by flow cytometry (as in Wan2012) despite negative standard ANA/anti-dsDNA?
  • Is the 3-month-old infant’s dengue infection primary (no pre-existing immunity) or does passive maternal antibody transfer interact with dengue pathogenesis in infants?
  • What is the prevalence of dengue-triggered MAS in endemic populations? This paper reports 3 cases but provides no denominator.

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