A fatal case report of antibody-dependent enhancement of dengue virus type 1 following remote Zika virus infection

Abstract

Background: Dengue virus (DENV) is endemic in many parts of the world. Antibody dependent enhancement (ADE) in DENV infections occurs when a person with primary immunity is infected by a second, different DENV strain. Antibodies to Zika virus (ZIKV), which emerged in the Western Hemisphere in 2015, are cross reactive with DENV and theoretically could provoke ADE in a DENV naïve individual.

Case presentation: DENV infection was suspected in a child who had recently returned from a one-month stay in the Dominican Republic. The child presented with fever, vomiting, abdominal pain, and in hypovolemic shock. Volume and pressor resuscitation were unsuccessful, and the child died less than 24 h after hospitalization. Laboratory results suggested an early acute first DENV infection since serum, plasma, and spinal fluid had DENV1 detected by polymerase chain reaction (PCR), yet the serum lacked IgG antibodies to DENV nonstructural protein 1 (NS1) of all four DENV serotypes. This acute DENV infection occurred in the presence of a remote ZIKV infection as determined by antibodies to ZIKV NS1 envelope by multiplex microsphere immunoassay and an exceptionally high plaque reduction neutralization titer to ZIKV. ZIKV IgG avidity index was high, confirming a past infection. DENV1 RNA was detected in all ten organs and tissues examined by PCR. The severe and fatal complications reported here suggest that a remote ZIKV infection may provoke an exaggerated immune response leading to hypovolemic shock when primarily infected by DENV1.

Conclusion: We report the first known patient in the United States with a rapidly progressive and fatal case of travel-associated DENV in which prior exposure to ZIKV likely played a role in triggering an ADE phenomenon. This association of prior ZIKV immunity and subsequent new dengue infection is a worrisome phenomenon and an important contribution to the body of knowledge on immunity to flaviviruses.

Keywords: Antibody dependent enhancement; Avidity assay; Case report; Dengue virus; Zika virus.

Fig. 1

Patient timeline. HA headache, AMS altered mental status, DIC disseminated intravascular coagulation

Fig. 2

Histopathology- Hematoxylin and eosin staining (magnification 400×) A Lung with alveolar macrophages containing intact erythrocytes (hemophagocytosis). B Spleen with markedly congested sinusoids. C Early, focal liver necrosis and sinusoidal hemorrhage. D Section of bone marrow with histiocyte containing intact erythrocytes (hemophagocytosis, green arrow) and red blood cell sickling (black arrow)

Fig. 3

a Multiplex microsphere immunoassay measurement of total antibodies to Zika envelope, Zika NS1, and the NS1 proteins of all four dengue serotypes are presented as the median fluorescence intensity (MFI) of 100 beads counted for each antigen coated beads on the Y axis. The target antigens are reported on the X axis. This multiplex analysis demonstrates past Zika infection. The dramatically lower level of antibodies to dengue NS1 proteins makes a past dengue infection unlikely. b Shows the virus being neutralized. Exceptionally high PRNT to Zika indicates past infection. The lower PRNT to DENV1 and DENV2 may indicate cross reaction of the Zika antibodies recognizing dengue since it is the envelope protein being neutralized