Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2

J Clin Immunol. 2021 Jul;41(5):987-991. doi: 10.1007/s10875-021-00986-9. Epub 2021 Feb 11.


Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome resulting from defective cytotoxicity. A previously healthy 3-month-old female presented with fever, irritability, abdominal distention, and tachypnea. She ultimately met all eight HLH-2004 diagnostic criteria, accompanied by elevated CXCL9. Initial empiric anti-inflammatory treatment included anakinra and IVIg, which stabilized ferritin and cytopenias. She had molecular and genetic confirmation of perforin deficiency and was started on dexamethasone and etoposide per HLH-94. She clinically improved, though CXCL9 and sIL-2Ra remained elevated. She was readmitted at week 8 for relapsed HLH without clear trigger and HLH-94 induction therapy was reinitiated. Her systemic HLH symptoms failed to respond and she soon developed symptomatic CNS HLH. She was incidentally found to have multifocal lung and kidney nodules, which were sterile and consisted largely of histiocytes and activated, oligoclonal CD8 T cells. The patient had a laboratory response to salvage therapy with alemtuzumab and emapalumab, but progressive neurologic decline led to withdrawal of care. This report highlights HLH foci manifest as pulmonary/renal nodules, demonstrates the utility of monitoring an array of HLH biomarkers, and suggests possible benefit of earlier salvage therapy.

Keywords: Hemophagocytic lymphohistiocytosis; biomarkers; cytokine storm; hyperinflammation; immunotherapy; perforin.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alemtuzumab / therapeutic use
  • Anti-Inflammatory Agents / therapeutic use
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Neutralizing / therapeutic use
  • Dexamethasone / therapeutic use
  • Etoposide / therapeutic use
  • Fatal Outcome
  • Female
  • Humans
  • Immunoglobulins, Intravenous / therapeutic use
  • Immunologic Factors / therapeutic use
  • Infant
  • Inflammation / diagnosis
  • Inflammation / drug therapy
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Lymphohistiocytosis, Hemophagocytic / diagnosis*
  • Lymphohistiocytosis, Hemophagocytic / drug therapy
  • Perforin / deficiency
  • Salvage Therapy


  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Emapalumab
  • Immunoglobulins, Intravenous
  • Immunologic Factors
  • Interleukin 1 Receptor Antagonist Protein
  • Perforin
  • Alemtuzumab
  • Etoposide
  • Dexamethasone

Supplementary concepts

  • Hemophagocytic lymphohistiocytosis, familial, 2