Open forum infectious diseases · 2026
Hemophagocytic Lymphohistiocytosis Criteria Overlap with Severe Malaria Features in Children.
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Kazinga Caroline, Namazzi Ruth, Batte Anthony, Cusick Sarah E, Datta Dibyadyuti, Opoka Robert O, Lintner-Rivera Michael, Jacob Shevin T, Mellencamp Kagan A, Kumar Ashish, John Chandy C, Conroy Andrea L
Аннотация
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome diagnosed using composite clinical and laboratory criteria. Several features used to classify HLH overlap with manifestations of severe malaria, raising uncertainty about the specificity and prognostic significance of HLH classification in this context. We examined the frequency of HLH and its association with mortality in children with severe malaria.
METHODS: We analyzed two cohorts of Ugandan children hospitalized with Plasmodium falciparum severe malaria (cohort #1, n = 461; cohort #2, n = 594). HLH was classified using the HLH-2004 criteria and the HScore. To address differences in laboratory availability, concordance analyses were performed using criteria assessed in both cohorts. Associations with in-hospital mortality were examined using logistic regression.
RESULTS: Features included in HLH diagnostic criteria were common in both cohorts. Hyperferritinemia (≥500 ng/mL) was present in >75% of children, whereas hypofibrinogenemia was uncommon (<2%). Using complete criteria, the frequency of HLH classification varied between cohorts (HLH-2004: 3.5% vs 13.0%; HScore >169: 0% vs 17.8%), but was similar in concordance analyses. Classification by HLH-2004 criteria was not associated with mortality in either cohort. In cohort #2, higher HScores were associated with increased unadjusted mortality (OR 3.04, 95%CI 1.57-5.86), although this association was attenuated after adjustment for markers of organ dysfunction (aOR 1.87, 95%CI .90-3.89).
CONCLUSIONS: Children with severe malaria frequently meet clinical and laboratory criteria used to classify HLH. However, HLH classification using current diagnostic frameworks was not independently associated with mortality, suggesting substantial overlap between HLH criteria and manifestations of severe malaria.
METHODS: We analyzed two cohorts of Ugandan children hospitalized with Plasmodium falciparum severe malaria (cohort #1, n = 461; cohort #2, n = 594). HLH was classified using the HLH-2004 criteria and the HScore. To address differences in laboratory availability, concordance analyses were performed using criteria assessed in both cohorts. Associations with in-hospital mortality were examined using logistic regression.
RESULTS: Features included in HLH diagnostic criteria were common in both cohorts. Hyperferritinemia (≥500 ng/mL) was present in >75% of children, whereas hypofibrinogenemia was uncommon (<2%). Using complete criteria, the frequency of HLH classification varied between cohorts (HLH-2004: 3.5% vs 13.0%; HScore >169: 0% vs 17.8%), but was similar in concordance analyses. Classification by HLH-2004 criteria was not associated with mortality in either cohort. In cohort #2, higher HScores were associated with increased unadjusted mortality (OR 3.04, 95%CI 1.57-5.86), although this association was attenuated after adjustment for markers of organ dysfunction (aOR 1.87, 95%CI .90-3.89).
CONCLUSIONS: Children with severe malaria frequently meet clinical and laboratory criteria used to classify HLH. However, HLH classification using current diagnostic frameworks was not independently associated with mortality, suggesting substantial overlap between HLH criteria and manifestations of severe malaria.