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


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.

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Hemophagocytic lymphohistiocytosis


Familial hemophagocytic lymphohistiocytosis


Hematopoietic stem cell transplantation


Variants of uncertain significance


Natural killer cell


Cytotoxic T lymphocyte


Soluble interleukin-2 receptor


Interleukin-18 binding protein


Central nervous system


Cerebrospinal fluid


Magnetic resonance imaging


Intravenous immunoglobulin


Hospital day


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SC is supported by R01HD098428 and the RK Mellon Institute for Pediatric Research. JD is supported by a Burroughs-Wellcome Physician-Scientist development award held by the University of Pittsburgh. MM-R is supported by the Marjorie K. Harmer Endowment for Research in Pediatric Pathology. JD is supported by T32HD071834.


SC has received research support for an ongoing clinical trial from AB2Bio, Ltd. All other authors have no financial relationships relevant to this article to disclose.

Author information




JES, JD, and SC conceived the study design. JES, CS, MRM, CS, SG, DT, and SC generated figures and collected data. JES and SC drafted the manuscript. All authors were involved in the critical revision of the article for important intellectual content and approved the final version.

Corresponding author

Correspondence to Scott W. Canna.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the University of Pittsburgh (STUDY20010099).

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Freely-given, written informed consent to participate in the study was obtained according the above-referenced protocol.

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Segal, J.E., Daley, J., Barnum, J. et al. Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2. J Clin Immunol (2021).

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  • Hemophagocytic lymphohistiocytosis
  • perforin
  • cytokine storm
  • biomarkers
  • hyperinflammation
  • immunotherapy