We are writing the present letter in reference to the article published by Morel and Ramirez,1 which reported the clinical signs and symptoms of 3 pediatric patients with dengue virus (DV) infection in Paraguay, a country in which this virus is endemic. The first case involved an 8-year-old boy in whom the disease was self-limiting. He required no treatment after a 14-day period during which the disease presented as fever, hepatosplenomegaly, tachycardia and bilateral pleural effusion, with positive DV serology. Serological tests for lupus anticoagulant, anticardiolipin, antinuclear and anti-DNA antibodies were all negative, and complement levels were normal. However, the clinical signs and symptoms in the other 2 cases were consistent with a macrophage activation syndrome (MAS). These cases involved a 3-year-old preschool boy and a 3-month-old male infant who had similar clinical signs and symptoms, characterized by fever and hepatosplenomegaly, in addition to anemia, leukopenia and neutropenia, and both responded favorably to glucocorticoids.1 The MAS presents clinically with cytopenia, organ dysfunction and coagulopathies due to the inappropriate inactivation of the macrophages. It has been related to autoimmune disorders in different diseases, mainly systemic juvenile idiopathic arthritis, and has been linked to other autoimmune processes, as well.2 Moreover, another case of MAS associated with dengue infection has been reported by Lai et al. The patient was a 55-year-old woman with neutropenia and lymphopenia, in addition to a myelogram showing evidence of hemophagocytosis. During her hospital stay, she was diagnosed as having nephrotic syndrome, and dengue infection was confirmed by a positive test for NS1 antigen and positive IgG and IgM serology, which demonstrated DV reinfection.3

Other cases of an association between autoimmune manifestations and DV infection have also been reported. Talib et al. described a case of systemic lupus erythematosus (SLE) and lupus nephritis triggered by DV, in which the serological test for NS1 antigen was positive. The diagnosis of SLE with lupus nephritis was confirmed because the patient met 4 of 11 diagnostic criteria of the American College of Rheumatology, among them, presence of antinuclear antibodies with a homogeneous pattern and positive test for anti-dsDNA.4 We found few reports on the interrelationship of DV with lupus nephritis and SLE. However, the case of Talib et al. could be related to a kidney disease associated with a positive test for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) or it may have developed as a lupus flare or de novo disease. Another report, from China, found an association between DV and ocular manifestations observed in young women, in whom DV infection provoked antibody production and immune complex deposition, with the subsequent development of retinal vasculitis.5

Antibody production played an important role in the pathogenesis of dengue. Several studies in animals and in hospitalized patients have shown that the generation of autoantibodies against platelets, endothelial cells and coagulation factors was correlated with disease severity and the development of hemorrhagic fever.6,7 In particular, the titers of antibodies to endothelial cells, analyzed by flow cytometry, peaked during the acute phase, and subsequently decreased; even so, in contrast to findings in other chronic infections, they remained detectable for several months. The autoantibody levels were higher in patients who had dengue hemorrhagic fever or dengue shock syndrome when compared to those with DV infection; moreover, these autoantibody levels were similar among serotypes DENV-2, 3 and 4.7 Another study reported the persistence of clinical symptoms 2 years after acute infection, associated with persistently high IgG levels and expression of the FcγRIIa gene polymorphism, together with the presence of immune complexes, positive test for antinuclear antibodies or rheumatoid factor, or high C-reactive protein levels.8

In countries with zones in which DV is endemic, this infection should be included in the differential diagnosis of any systemic disease, especially in the pediatric population, as the literature reviewed showed an increase in the incidence of atypical symptoms. Manifestations reported in clinically atypical cases in countries in which DV is endemic are related to systemic presentations, including hepatic disorders (27%), acalculous cholecystitis (9%), pancreatitis (9%), pulmonary conditions (9%) and cardiovascular problems (7%).9

In conclusion, we consider the report by Morel and Ramírez,1 to be an important contribution. These authors have also conducted previous studies on the association between clinically evident autoimmunity and DV infection described above. Therefore, larger studies should be performed in populations in which this disease is endemic to better characterize the possible consequences of exacerbation of autoimmunity that can occur in these individuals over time.