Dengue hemophagocytic syndrome: A systematic review and meta-analysis on epidemiology, clinical signs, outcomes, and risk factors

Rev Med Virol. 2018 Nov;28(6):e2005. doi: 10.1002/rmv.2005. Epub 2018 Aug 15.


We systematically searched and meta-analyzed the epidemiological characteristics, frequency of clinical signs, and outcomes of dengue-associated hemophagocytic lymphohistiocytosis. Ten electronic databases were searched systematically plus manual search of reference lists to identify relevant articles published until May 2017. The highest number of reported cases were from South-East Asia region (62 cases), followed by Western Pacific region (20 cases), and America (31 cases). The term "dengue hemorrhagic fever" predominated in studies that used the World Health Organization 1997 definition (59.7%), whereas "severe dengue" predominated in studies using the World Health Organization 2009 definition (76.8%). Among 122 cases, fever, splenomegaly, hepatomegaly, anemia, thrombocytopenia, and serum ferritin ≥500 μg/L were likely to report by articles representing by large sample size. The pooled proportion of these findings were as follows: fever 97.2%, hepatomegaly 70.2%, splenomegaly 78.4%, thrombocytopenia 90.1%, anemia 76.0%, and serum ferritin ≥500 μg/L 97.1%. This study highlighted a high case fatality rate (14.6%) and co-infection among dengue hemophagocytic lymphohistiocytosis patients. We suggest that long fever duration, persistent thrombocytopenia, elevated serum ferritin, and lactate dehydrogenase levels could be good diagnostic indicators for dengue-associated hemophagocytic syndrome. Bone marrow aspiration could be used as one criterion for diagnosis but is not obligatory. Further research is needed to examine the possible risk difference for development of hemophagocytic syndrome and to explore potential relationships between specific dengue classifications and dengue-associated hemophagocytic syndrome.

Keywords: HLH; clinical signs; dengue hemophagocytic syndrome; epidemiology; macrophage activation syndrome; outcomes; risk factors.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Americas / epidemiology
  • Asia, Southeastern / epidemiology
  • Dengue / complications*
  • Humans
  • Lymphohistiocytosis, Hemophagocytic / epidemiology*
  • Lymphohistiocytosis, Hemophagocytic / mortality
  • Lymphohistiocytosis, Hemophagocytic / pathology*
  • Pacific Islands / epidemiology
  • Risk Factors
  • Survival Analysis
  • Treatment Outcome