Hyperinflammatory syndromes in primary mitochondrial disease: A three-center case series and focused review

Primary mitochondrial diseases (PMtD) are increasingly recognized to involve clinically meaningful immune dysregulation in addition to bioenergetic failure. Hyperinflammatory syndromes, including secondary hemophagocytic lymphohistiocytosis (HLH) and related cytokine-mediated inflammatory states, remain underrecognized complications of PMtD, and the mechanisms linking mitochondrial dysfunction to pathologic inflammation are incompletely understood.

We report three individuals with genetically confirmed PMtD evaluated at three academic medical centers who developed severe hyperinflammatory syndromes. Clinical, laboratory, treatment, and outcome data were retrospectively abstracted from the medical record using a standardized framework. We also performed a focused narrative review of the literature on hyperinflammation in mitochondrial disease.

Individual 1 had pyruvate dehydrogenase complex deficiency (PDCD), due to a PDHA1 variant and developed infection-associated HLH at age 9 years, with ferritin 17,203 ng/mL and bone marrow hemophagocytosis. He met 6 of 8 HLH-2004 criteria and had an HScore of 303 (>99% probability of HLH). He survived the index episode with corticosteroid-based therapy but experienced recurrent inflammatory decompensations and later died. Individual 2 had POLG-related mitochondrial disease and developed HLH at age 8 years during presumed viral-triggered neurologic deterioration in the setting of pre-existing hepatic vulnerability. He met 6 of 8 HLH-2004 criteria, had an HScore of 233 (>98% probability of HLH), and showed an initial biomarker response to emapalumab, but ultimately died of multiorgan failure. Individual 3 had MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; due to an m.3243 A>G variant in MT-TL1 and developed a sterile interferon (IFN)-driven hyperinflammatory syndrome during a stroke-like episode (SLE), with markedly elevated serum soluble interleukin (IL)-2 receptor (sIL-2R), IL-6, IL-10, C-X-C motif chemokine ligand 9 (CXCL9), and cerebrospinal fluid (CSF) neopterin, without meeting full HLH-2004 criteria (fulfilling only 2/8 criteria). He had minimal response to intravenous immunoglobulin (IVIg) but showed sustained clinical and biomarker improvement with anakinra and is alive, age 15 years at the time of this publication.

PMtD may be associated with a predisposition to a spectrum of hyperinflammatory syndromes ranging from classic secondary HLH to noncanonical sterile cytokine-mediated inflammation that falls below formal HLH thresholds. These complications may reflect mitochondrial danger signaling, inflammasome activation, engagement of the IFN pathway, and defective immunometabolic regulation. Early recognition and targeted immunomodulatory therapy may be critical to improving outcomes.