Link Between HLH Reactivation, Refractoriness, and Influenza

Pathophysiological Connection

Influenza virus infection can trigger severe hyperinflammatory responses leading to HLH development or reactivation, characterized by pathologic immune activation and hypercytokinemia 2

HLH should be suspected in patients with influenza who develop persistent fever despite antimicrobial therapy, unexplained cytopenias, organomegaly, and disproportionate inflammatory response 1, 3, 4
Diagnostic workup should include ferritin levels, often markedly elevated 5
The American Society of Hematology recommends diagnostic workup to include soluble CD25 (IL-2 receptor) levels and complete blood counts 2

Influenza-triggered HLH can become refractory to standard treatments, contributing to the high mortality rate in adult HLH, according to the American College of Physicians 1
Refractoriness may be related to persistent viral replication, acquired immunodeficiency, and secondary infections 1, 2, 5

The American College of Cardiology is not applicable here, however, the management approach for influenza-associated HLH includes initiation of antiviral therapy and consideration of corticosteroids to control hyperinflammation 1, 6
Intravenous immunoglobulin may be beneficial in the treatment of influenza-associated HLH 1, 6
Etoposide-based regimens may be necessary for refractory cases, particularly in rapidly deteriorating patients, as recommended by the European Society for Medical Oncology 1, 6

Regular monitoring of cell counts, viral load, and liver function tests is necessary 1, 2, 3
Weekly reevaluation of the need for continued etoposide therapy in patients requiring this treatment is recommended by the National Comprehensive Cancer Network 7

The European Hematology Association recommends vigilance for secondary infections, which are a major cause of mortality in patients with HLH 1, 5
In patients with malignancy, differentiation between "malignancy-triggered HLH" and "HLH during chemotherapy" is necessary, as treatment approaches differ markedly, according to the American Society of Clinical Oncology 8