Hemophagocytic Lymphohistiocytosis Gene Variants in Severe COVID-19 Cytokine Storm Syndrome

Severe COVID-19 infection resulting in hospitalization shares features with cytokine storm syndromes (CSSs) such as hemophagocytic lymphohistiocytosis (HLH). Various published criteria were explored to define CSS among patients (n = 32) enrolled in a COVID-19 clinical trial. None of the patients met HLH-04 or HScore criteria, but the ferritin to erythrocyte sedimentation rate (ferritin-ESR) ratio and the COVID-19 cytokine storm score (CSs) identified 84% and 81% of patients, respectively. As 30-40% of patients in published secondary HLH cohorts possess rare heterozygous mutations in familial HLH (fHLH) genes, whole genome sequencing was undertaken to explore immunologic gene mutation associations among 20 patients enrolled in the trial. Rare mutations in fHLH genes were identified in 6 patients (30%), and 4 patients (20%) possessed rare mutations in <i>DOCK8</i> (a novel CSS gene). Foamy viral transduction of the 3 <i>DOCK8</i> missense mutations into NK-92 natural killer (NK) cells diminished NK cell cytolytic function, a feature of HLH. This severe COVID-19 cohort, like others, shares CSS features but is best identified by the ferritin-ESR ratio. Rare heterozygous CSS gene (fHLH genes and <i>DOCK8</i>) mutations were frequently (45%) identified in this severe COVID-19 cohort, and <i>DOCK8</i> missense mutations may contribute to CSS via diminished lymphocyte cytolytic activity.